Polymeric Interventions for Microbial Infections: A Review - Molecular

Review Cite This: Mol. Pharmaceutics XXXX, XXX, XXX−XXX

Polymeric Interventions for Microbial Infections: A Review Melanie A. Hutnick and Jonathan K. Pokorski* Department of Macromolecular Science and Engineering, Case School of Engineering, Case Western Reserve University, Cleveland, OH 44106, United States ABSTRACT: The world is facing a growing crisis of microbial infections, where resistant strains are rapidly outpacing the development of new therapeutics. In an effort to combat this, the polymer community is developing new ways to improve upon drug delivery, synthesizing novel antimicrobial polymers, and using polymer technology to harness combination therapies. This review focuses primarily on the use of polymers to treat both bacterial and fungal infections in recent years. A bevy of work has illustrated that polymer technologies can have a huge impact in treating bacterial infections. However, harnessing polymers to deliver antifungals or as stand-alone therapeutics lags far behind that of interventions for bacterial infections. Fungal infections can be crippling to both human health and the agricultural community, making this area ripe for drug delivery technologies. This review describes recent work and highlights opportunities for bacterial and fungal treatment using soft matter. KEYWORDS: microbial infections, polymers, bacterial and fungal infections, nanoparticle drug delivery, multidrug resistant bacteria

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INTRODUCTION Antimicrobial agents are active therapeutic molecules used to kill or inhibit the growth of pathogenic microbes in living systems. Several antimicrobial therapeutics have been investigated to treat infections caused by bacteria, fungi, and protists, ranging in physicochemical and pharmacological approaches. These drugs typically operate by binding to a biological macromolecule that is specific to the microorganism and interfering with cellular metabolism, in turn altering biomolecular synthesis or cellular functions. Effective antimicrobial therapeutics interfere with cellular function at low effective doses while having negligible toxic side effects to normal host function. There is a need for better antimicrobial agents toward all microorganisms due to rapidly evolving drug resistance and the slow pace of clinical introduction of new antimicrobial agents. The overuse and abuse of antibiotics has markedly increased the rapid rise of antimicrobial resistance. Roughly 20% of drug resistant infections are foodborne illnesses, which is heavily influenced by the abuse of antibiotics administered in the farming of livestock.1−3 Additionally, overprescribed antibiotics without definitive proof of a bacterial infection have vastly contributed to this issue. Antibiotic resistance is outpacing the development of novel antibiotics and posing one of the biggest threats to global health, food security, and development.1 Antimicrobial resistance can cause severe morbidity and mortality. Solely in the US, antibiotic resistance accounts for 2 million infections, 8 million hospitalization days, 23 000 deaths, which results in $20 billion in healthcare costs, and $35 billion in societal costs annually.4 As antimicrobial drug resistance continues its ever-imposing threat on mankind, innovative approaches must be developed rapidly to combat these recalcitrant microbes. One technique that is being © XXXX American Chemical Society

pursued in the literature is nanoparticulate drug delivery to microorganisms to enhance drug accumulation and efficacy while reducing side-effects.5,6 This approach is well-established for the treatment of a wide range of cancers, however, the field of nanoparticle delivery for microbial infections is still in its infancy. This review will focus on recent advances in soft-matter nanoparticles and polymer technology for the treatment of both bacterial and fungal infections.

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NANOPARTICLE DRUG DELIVERY Nanoparticle drug delivery vehicles are widely studied systems because their versatile nature is attractive to a number of pharmacological issues. There are two predominant modes of delivering payloads to a pathological site: passive and active targeting. Passive drug delivery takes advantage of the prolonged retention time of nanoparticles in the bloodstream. The longer residence time can allow for the nanoparticle agent to more readily accumulate in infected regions.7 Active targeting uses site specific ligands to bind nanoparticles to a site of disease.4 Dependent on the system, nanoparticles can be neutral or charged, ligand functionalized, assume various architectures, solubilize, and encapsulate hydrophobic or hydrophilic drugs (Figure 1). Their small size (1−100 nm) and high surface area-to-volume ratio promote the likelihood for specific interaction with pathogens and membrane displayed Special Issue: Click Chemistry for Medicine and Biology Received: March 30, 2018 Revised: May 10, 2018 Accepted: May 15, 2018

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DOI: 10.1021/acs.molpharmaceut.8b00342 Mol. Pharmaceutics XXXX, XXX, XXX−XXX

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Molecular Pharmaceutics

Figure 1. Soft-matter nanoparticles for drug delivery. (A) Liposome, (B) polymeric nanoparticle, and (C) dendrimer. Reproduced with permission from ref 5. Copyright 2014 Wiley.

Figure 2. Effect of encapsulated carbapenem on carbapenem-resistant bacteria. (A) Degradation of carbapenem by carbapenemases. (B) Effect of carbapenemases on free imipenem/cilastatin (IMP), encapsulated IMP in PCL nanoparticles, and encapsulated in IMP in PLGA against (B) K. pneumoniae, (C) P. aeruginosa, and (D) E. coli. Reproduced with permission from ref 21. Copyright 2017 BioMed Central.

comprehensive reviews of NO delivery that could be complementary to this article.12−14

biological markers. Additionally, they can surpass most physiological barriers to deliver payloads to intended targets.8−10 Nanoparticles increase bioavailability, increase local drug concentration, decrease repeated dose, reduce side effects, localize at pathogenic sites for prolonged delivery, and are amenable for targeted delivery.11 As microbes develop tolerance and resistance to traditional antimicrobial therapeutics, nanoparticle drug delivery vehicles can aid in delivering concentrated doses of therapeutics to an infected site. In doing so, drug delivery vehicles can revive therapeutics that were once deemed no longer effective. Moreover, targeted drug delivery vehicles can be selective for specific pathogenic cell lines mitigating side effects and toxicity concerns. Lastly, nanoparticles provide the opportunity to package multiple drugs in a single particle that could overcome resistance and protect sensitive therapeutics from the body’s natural degradation mechanisms. However, it is worthwhile to consider degradation and/or clearance pathways for macromolecular delivery vehicles. While low molecular weight polymers can undergo renal filtration and be excreted, larger macromolecules or nanoparticles likely need to be designed with a degradation mechanism in mind. Vinyl polymers typically do not have a biological degradation pathway, which may lead to excess accumulation of antimicrobials in off-target organs, such as the liver and spleen. Along these lines, the implementation of clever degradation pathways presents the opportunity to deliver small molecule antimicrobials, such as nitric oxide (NO). While not explicitly covered in this review, we refer the reader to

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MULTIDRUG RESISTANT BACTERIA

There is a special urgency to develop novel or enhanced therapeutics for ESKAPE pathogens (i.e., Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, and Enterobacter spp.), as these species comprise the majority of hospital-derived infections and have developed mechanisms to “escape” current antimicrobial therapies.15,16 Antimicrobial drug resistance is the ability for a microorganism to resist the cytotoxic effects of a drug and continue to proliferate. There are four modes of drug resistance in microorganisms. First, selective permeability of the microbial cell membrane or wall reduces transport of the active agent thereby diminishing its concentration at the target site. For bacteria, many efflux pumps on the membrane can transport antibacterial agents out of the cell.17 Second, bacterial drug resistance is largely due to drug inactivation. Enzymatic modification of the drug itself has led to antibiotic resistance, as is the case for oxyiminocephalosporin-resistant P. aeruginosa and aminoglycoside-resistant A. baumannii.18 Third, because many drugs function by targeting a specific biological macromolecule in the microbe, most commonly proteins, any mutation in the target site renders the drug less effective; this is true for methicillin-resistant S. aureus, vancomycin-resistant Enterococci spp., and macrolide-resistant Streptococcus pneumoniae.18 Fourth, altered metabolic pathways have allowed bacteria to evade antibiotic annihilation. Sulfonamide-resistant B


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Figure 3. Single-chain amphiphilic random copolymers folding upon the additional water due to hydrophobic interactions to form antimicrobial SCPNs. Reproduced with permission from ref 22. Copyright 2017 American Chemical Society.

bacteria lack the need for p-aminobenzoic acid bypassing the mechanism of inhibition for sulfonamides.19 These mechanisms are responsible for an imminent crisis as resistance is far out pacing the development of novel antibiotics. This is the primary motivation for the development of drug delivery vehicles for microbial infections.

regained against strains once regarded as carbapenem-resistant. However, these are still preliminary in vitro results. Further studies, including in vivo models, must be performed before definitive claims can be made. Many antimicrobial drug delivery vehicles incorporate hydrophobic and cationic motifs into their design to mimic the properties of antimicrobial peptides. Typically, cationic peptides bind to the anionic phospholipids comprising the cell membranes, followed by penetration into the cell wall and insertion into the lipophilic cell membrane. Nguyen et al. sought to mimic these properties with single-chain polymeric nanoparticles (SCPN) comprised of oligoethylene glycol, hydrophobic, and amine groups synthesized to fold in aqueous systems due to intramolecular hydrophobic interactions (Figure 3). When tested for antimicrobial activity, the particles were effective at μM levels for P. aeruginosa, killing both planktonic cells and biofilms within an hour. This system is highly tunable by varying the monomer composition, which in turn can vary the degree of cell membrane disruption. To assess the efficacy of this system, the varying SCPNs were tested relative to the activity of colistin, often considered the last line of defense for antimicrobial agents against Gram-negative bacteria. Consistently, the SCPNs matched or outperformed colistin in in vitro assays, which bodes well for its translation to drug resistant strains. Moreover, SCPNs exhibited the ability to kill and disperse biofilms, a trait often lacking for traditional antimicrobial therapeutics.22 These promising results have inspired researchers to conduct in vivo studies currently underway. Recently, the Boyer group sought to expand on this elegant work by investigating the role of polymer architecture and its effect on antibacterial activity relative to hemolysis. The monomer compositions were similar to that described above; however, the researchers varied the polymer architecture between random terpolymers, block architectures, and hyperbranched nanoparticles.23 The results were quite interesting, where block architecture negated antibacterial activity against Gram-negative bacteria. Furthermore, the chain length played a

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PASSIVE ANTIBACTERIAL DRUG DELIVERY STRATEGIES Passive drug delivery vehicles for microbial infections use polymeric systems to encapsulate a drug to improve its therapeutic index. These systems lack targeting groups to select a specific site or cell line and rely on improved pharmacokinetics to increase accumulation at the infected site. Though these systems can be rudimentary, their simplicity has laid the foundation for the drug delivery canon. For antibiotic delivery, passive systems are often explored as the initial means of reviving “useless” antibiotics, as is the case for carbapenems. Carbapenems are a family of highly potent, broad-spectrum, βlactam antibacterial agents that were once widespread in hospital settings. They possessed great stability against βlactamases produced by drug-resistant bacteria. However, in 2001, it was discovered that Enterobacteriaceae and Pseudomonas had evolved resistance against carbapenems through hydrolyzing enzymes known as carbapenemases, among other mechanisms (Figure 2A).20 Shaaban et al. encapsulated imipenem/cilastatin in polymeric nanocapsules using double emulsion evaporation of polylactide-co-glycolide (PLGA) and poly ε-caprolactone (PCL). While cilastatin does not exhibit any antimicrobial properties, it inhibits the enzymatic degradation by renal dehydropeptidase of imipenem, a type of carbapenem, thus reversing resistance.21 When tested against resistant isolates of P. aeruginosa, K. pneumoniae, and E. coli, the PCL nanoencapsulation exhibited greater antibacterial properties in all antimicrobial assays than the PLGA and free drug samples (Figure 2B−D).21 Therefore, by encapsulating carbapenems in PCL nanoparticles, their efficacy can be C


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Molecular Pharmaceutics role in antibacterial activity, with slightly longer chains showing modestly improved properties. Most interestingly, however, was the fact that the hyperbranched architecture showed the best selectivity for bacteria versus hemolysis, even if antibacterial activity was slightly depressed. This work was rapidly followed by a much more detailed study investigating block length and sequence order to develop quasi-sequencecontrolled polymers for antimicrobial activity.24 The authors made an impressive array of polymers using photoinduced electron transfer-reversible addition−fragmentation chain transfer (PET-RAFT) polymerization incorporating hydroxethyl acrylamide, phenylethyl acrylamide, and aminoethyl acrylamide. The outcome of this study was that polymer composition could be tuned for pathogen specificity. Furthermore, monomer distribution played a great role in determining hemolytic versus antibacterial activity. The results of this work are certainly an exciting step in tailoring antimicrobial polymers to be pathogen-specific and could represent a new approach to overcome drug resistance. Iron plays an essential role in the formation of bacterial infections as it acts as a cofactor for bacterial respiration, nitrogen fixation, photosynthesis, and DNA synthesis and repair.25 Depleting iron weakens bacteria and can behave as an adjuvant when coupled with antibiotics. However, current iron chelating therapeutics, i.e. Deferasirox, can damage the kidneys or liver and cause internal bleeding. Multivalent polymer gels were synthesized from cross-linked polyallylamine (PAI) modified with 2,3-dihydroxybenzoic acid (DHBA) to sequester iron in P. aeruginosa growth media (Figure 4). While these PAIDHBA gels were effective at arresting growth in media, the gels required synergistic treatment with an antibiotic (i.e., ciprofloxacin or gentamicin) to reduce cell viability.26 Though this method cannot be used on its own to effectively kill multidrug resistant bacteria, when combined with another treatment modality, the two may work in synergy to combat recalcitrant infections. The polymer gels can retard bacterial growth, while the antibiotic can eradicate the infection.

Figure 4. Synthesis of iron-sequestering polymers (top). As iron is sequestered from the bacterial media, growth is inhibited as determined by colony forming units (bottom). Reproduced with permission from ref 26. Copyright 2015 American Chemical Society.

allowed for effective magnetic filtering of E. coli from a liquid sample (Figure 5B).4 Bacterial separation can have implications in blood filtering. Wong et al. developed a heteromultivalent design to bind the lipopolysaccharides on the surface of the Gram-negative cell walls. Poly(amidoamine) (PAMAM) generation 5.0 (G5) dendrimers are multivalent, biocompatible, monodisperse molecules that are widely studied for their ideal drug delivery properties. PAMAM was functionalized with both polymyxin B (PMB), as the primary high affinity binding ligand, and a PMBmimicking dendritic branch, acting as an auxiliary low affinity binding ligand. Lipopolysaccharide (LPS) binding was assessed via surface plasmon resonance studies using an LPSimmobilized cell wall model and confocal microscopy. The most promising of these samples was PAMAM functionalized with PMB and ethanolamine (EA)-terminated branches, which adsorbed to E. coli cells (Figure 6), exhibited potent bactericidal activity, and had a high binding affinity 2 orders of magnitude greater than the unconjugated PMB.28 Peptidoglycans of Gram-positive bacteria are often targeted with vancomycin. In a study performed by Teratanatorn et al., they elucidated the implications of architecture on antibiotic drug delivery by comparing the antimicrobial effects of linear versus highly branched poly(N-isopropylacrylamide) (PNIPAM) functionalized with vancomycin. Despite similar vancomycin loading levels, the linear system (0.028 mg/mL) did not aggregate S. aureus, while the highly branched system

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ACTIVE ANTIBACTERIAL NANOPARTICLES Actively targeted drug delivery vehicles were first introduced by Paul Ehrlich with his “magic bullet” concept, which would have drugs go directly to their intended targets, at the right concentration, for the appropriate length of time.27 However, in the case of systemic administration, drugs reach their intended target upon circulation in the bloodstream, often resulting in accumulation in other organs. Though no known drug or vehicle directly goes to the site of interest, advances have been made to develop nanoparticles that are highly specific in their interactions to promote site specific binding.27 In one such example, Lu et al. demonstrated the ability to synthesize polystyrene-block-polyethylene glycol (PS-b-PEG) copolymer self-assemblies via flash nanoprecipitation with further modification of the nanoparticles to bind the surface of both the Gram-positive and Gram-negative bacteria. Zinc(II)-bis(dipicolylamine) (ZnDPA)-decorated particles targeted phosphatidylserine present on the surface of both Gram-negative (e.g., E. coli and P. aeruginosa) and Gram-positive bacteria (e.g., S. aureus) (Figure 5A). Moreover, these motifs expressed on the surface of bacteria are not present on healthy mammalian cells.4 ZnDPA-modified nanoparticles were able to bind all three bacteria; however, they were not able to bind as strongly to P. aeruginosa. Additionally, ZnDPA-functionalized nanoparticles were loaded with hydrophobic iron oxide (FeAO), which D


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Figure 5. Magnetic bacteria targeted nanoparticles for filtering of liquid samples. (A) Schematic of Zn nanoparticles targeting phosphatidylserine on the bacterial wall. (B) Schematic of immobilized Fe-loaded magnetic nanoparticles binding bacteria from liquid samples for potential blood filtering applications. Reproduced with permision from ref 4. Copyright 2017 Springer.

Figure 6. Schematic for adsorption of PAMAM dendrimers functionalized with PMB and EA adhering to a Gram-negative bacterium. LPS = Lipopolysaccharide, OM = outer membrane, PG = peptidoglycan layer, and IM = inner membrane. Reproduced with permission from ref 28. Copyright 2015 Royal Society of Chemistry.

tion 3D electron density maps of E. coli (Figure 7C). Additionally, nanostructures exhibited high activity, low toxicity, and target specificity because they recognized the differences in membrane structure and lipid composition. These unique characteristics make nanostructures a highly attractive platform for novel antimicrobial agents.30 Another approach utilizing nanostructures is the work being done on structurally nano-engineered antimicrobial peptide polymers (SNAPPs) against multidrug resistant (MDR) Gramnegative bacteria.31 SNAPPs are prepared via an N-carboxyanhydride ring-opening polymerization of lysine and valine from the termini of PAMAM G2 or G3 dendrimers, resulting in star shaped polymers. These architecturally unique structured peptide−polymer systems have exhibited impressive sub-μM antimicrobial activity against all of the ESKAPE pathogens and colistin-resistant (CMDR) pathogens, while exhibiting low cytotoxicity toward mammalian cells. SNAPPs have demonstrated the ability to effectively combat CDMR A. baumannii for in vivo mice studies. SNAPPs interact with the outer membrane, peptidoglycan, and cytoplasmic layers of Gramnegative bacteria via electrostatic interactions killing the pathogen by several potential mechanisms (Figure 8). Fragmentation or destabilization of the outer membrane may disrupt the cytoplasmic membrane causing an unregulated ion exchange. They may also induce apoptotic-like death pathways, which lyse the bacterium.31

did (0.025 mg/mL). Vancomycin’s binding target is the D-AlaD-Ala dipeptide, which inhibits cell wall synthesis. To assess the polymeric systems’ abilities to bind the dipeptide, microcalorimetry was performed and indicated both systems are equally as effective at binding the peptide.29 These studies indicate targeted nanoparticle delivery elevates local concentrations of antimicrobials near bacteria, which increases drug bacteriostatic and bactericidal activities.

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NANOSTRUCTURES AS ANTIBACTERIALS A novel approach toward combating drug resistant microorganisms is inspired by bacteriophages, or viruses that infect bacteria. Bacteriophages utilize their unique nanoarchitecture to infiltrate bacteria in an efficient and selective manner. To better understand the role of nanostructure morphology on antibacterial properties, spherical and rod-like polymer brushes were synthesized to mimic two basic structural components of bacteriophages (Figure 7).30 Densely packed hydrophilic poly(4-vinyl-N-methylpyridine iodide) branches were synthesized via a combination of controlled radical polymerizations. Though traditional membrane active antimicrobials require a balance between cationic character and hydrophobic nature, this does not hold true upon the introduction of nanomorphology. Despite being comprised of hydrophilic polymers, the nanostructures acted as pore formers in bacteria but not in mammalian cells, as was demonstrated by Fourier reconstrucE


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Others have also demonstrated the promise of highly cationic star polymers to combat MDR microbes via polylysine polyglucosamine functionalized star arms while mitigating hemolytic concerns.36 Metaphilic helical peptides are poly(arginine) analogues formed along a neutral helical backbone with hydrophobic side chains extending from the rod and functionalized with a guanidinium group or alkyl chain “clicked” on the termini, resulting in a bottlebrush-like architecture. Computer simulations suggest the side chains can rearrange in different environments, which may allow for the shape to deform upon interaction with the cell membrane unlike traditional antimicrobial peptides. This could potentially translate as an antimicrobial therapeutic or drug delivery system.37 Additionally, Pranantyo et al. synthesized four-arm glycopolymers-polylysine conjugates via atom transfer radical polymerization, ring opening polymerization, and click chemistries to generate nanoparticles that exhibited bactericidal properties for Gram-negative and Gram-positive bacteria.38 The previous examples utilizing nano-architecture to inhibit bacterial growth show great promise since, to our knowledge, there are no known resistant pathways against these approaches. We envision that inactivation of these antimicrobials, could certainly be feasible if broadly used; however, the evolutionary steps to develop resistance would surely be a greater challenge than the inactivation of a simple small molecule therapeutic.

Figure 7. Bacteriophage mimicking nanostructures as antimicrobial agents. (A) Spherical and rod-like PMBs as base units inspired by bacteriophage design with chemical structures. (B) Blue = poly(4vinyl-N-methylpyridine iodide) branches, red = PMB core, green = lipid tails, and yellow and pink = headgroups of anionic and ethanolamine termini. (C) Example of nanostructured PMBs remodeling E. coli membranes by forming pores. At the center of the holes are PMB rods. Reproduced with permission from ref 30. Copyright 2017 American Chemical Society.

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FUNGAL INFECTIONS Of the nearly 1.5 million species of fungi in the world, 300 species are responsible for >1.7 billion infections worldwide.39−46 The most common pathogens for systemic infections are Candida, Aspergillus, and Cryptococcus, all of which can be acquired in a variety of ways. More distressingly, these pathogens are rapidly developing new resistant strains.47 Increasing occurrences of systemic mycoses are primarily due to one of three reasons: increase in immunosuppressed patients due to HIV, cancer, and organ transplants; catheter-related bloodstream infections; and increase in the use of broad spectrum antifungals for prolonged periods of time, leading to resistance. Not only do these resistant strains directly impact human health, they also pose a threat to agricultural sustainment.48 As the agricultural industry seeks to eradicate fungal infections to sustain crop yield, the industry is exacerbating the problem of resistance. The resistant agricultural strains are being seen more and more in the clinic. As such, it is imperative to develop new strategies to combat fungal infections that threaten human health and the food supply. This need becomes even more dire, since currently approved antifungals only operate on four pharmacological targets. One such target is the cell wall. A class of compounds, known as echinocandins, inhibit 1,3-β-glucan synthase, which is necessary for cell wall formation. Another tactic is the destabilization of the plasma membrane by polyenes. Polyenes bind the ergosterol of the plasma membrane, causing the formation of pores, compromising the membrane, and resulting in apoptosis. Azoles inhibit 14α-demethylase, which is responsible for the synthesis of ergosterol, disrupting the formation of the plasma membrane. Lastly, 5-fluorocytosine employs permeases to transport through the cell wall and inhibit DNA and RNA synthesis.49 Of these, only azoles and 5fluorocytosine can be administered orally, making administration and patient compliance key challenges. Furthermore, a large subset of these therapeutics result in nephrotoxicity if

Antibiotics that inhibit a particular cell function often leave the cell wall intact imparting the opportunity for the bacteria to alter and develop antibiotic resistance. Antibacterial agents, whose strategy is to disintegrate the cell membrane, accomplish bacterial cytotoxicity with less opportunity for the development of drug resistance. Controlled polymerization by N-carboxyanhydrides (NCA) allows polypeptides to be synthesized on a large scale and at low cost, making them a viable approach toward combatting drug resistant microbes.32 Unfortunately, these new peptides have exhibited a high degree of cytotoxicity in clinical trials due their highly cationic nature. When these peptides form self-assembled nanostructures, it can increase biocompatibility.33 Antimicrobial peptide-based copolymer micelles of poly(L-lactide)-block-poly(phenylalanine-stat-lysine) with the PLLA units forming the core and the polypeptide chains acting as the corona were investigated for antibacterial properties. Transmission electron microscopy illuminated the mechanistic physical damage imparted on the bacterial membrane, causing cell rupture and death.34 Peptide-grafted hyperbranched polymer self-assemblies of nanosheets have demonstrated weak positive charges (+6.1 mV) that allow the nanostructure to adhere to the bacterial surface but remain biocompatible. Nanosheets were synthesized to be larger than bacteria, providing a greater surface area for contact with the microbes and “wrapping” them in the nanosheet followed by penetration of the membrane (Figure 9). This approach allowed for very low minimum inhibitory values (16 μg/mL) for E. coli and S. aureus, while reducing the cationic charge to promote biocompatibility.35 F


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Figure 8. Mechanism of SNAPP nanostructures disrupting the cell wall and membrane of multidrug resistant bacteria. SNAPPs interact with the outer membrane (OM), peptidoglycan layer, and cell membrane (CM) of Gram-negative bacteria via electrostatic attractions causing fragmentation or destabilization of the OM, disrupting the CM, thereby lysing the cell causing cell death. Reproduced with permission from ref 31. Copyright 2016 SpringerNature.

Figure 9. Antimicrobial self-assembly nanosheets “wrapping” and penetrating bacteria causing cell death via lysis. Reproduced with permission from ref 35. Copyright 2016 American Chemical Society.

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ANTIFUNGAL NANOPARTICLES Amphotericin B (AmB) is the “gold-standard” antifungal due to its broad-spectrum activity against pathogenic fungi.49−51 AmB possesses both an amphipilic nature due to the apolar and polar

prescribed for prolonged times. As outlined below, there is a great need for delivery systems to improve upon these traditional antifungals and/or to develop combination therapies to combat resistance. G


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Figure 10. Anionic ring-opening synthesis of antifungal nylon-3 polymers. Reproduced with permission from ref 64. Copyright 2017 American Society for Microbiology.

Lastly, the authors suggest that the uptake into macrophages is critical for developing a reservoir of the therapeutic, which should hold true for all nanosized formulations upon intravenous injection. Several papers have followed up on this strategy by developing new polymer encapsulants for AmB. Bocca et al. utilized a blend of poly(lactic acid) (PLA) and poly(glycolic acid) (PGA) to formulate nanoparticles on the order of ∼300 nm through emulsion-based strategies. Similarly, they found that the formulation was equally efficacious as commercial standards with lessened nephrotoxicity.57 Another example describes AmB encapsulated within ∼120 nm particles comprised of D -α-tocopheryl polyethylene glycol 1000 succinate (TPGS)-block-PCL-ran-PGA, which the authors deemed PLGA-TPGS.58 The results of this study were impressive in mitigating toxicity (increasing LD50 by ∼4-fold) and hemolytic activity. Not surprisingly, AmB reduced fungal burden the most in the liver and kidney, with equivalent efficacy to commercial formulations in other organs. It is becoming clear that these types of strategies are unlikely to improve the efficacy of AmB; however, they greatly improve the safety profile, potentially allowing for increased dosing. Another drawback that must be overcome is tissue specificity; nano- and microparticles are almost exclusively trafficked to the liver and spleen, making systemic treatment with nanoparticle systems a significant challenge. A more recent advance used a triblock copolymer as both an active agent against biofilms and as an encapsulant.59 Biofilms are a heterogeneous community of cells that adhere to a host cell or biomaterial surface encased by an extracellular matrix.60,61 These surface-associated cell communities pose a serious potential health risk when formed on medical devices. It is estimated that 65% of all catheter-derived infections are subsequent of biofilm formation.62,63 Lin et al. utilized a methoxypolyethylene glycol-poly ε-caprolactone-graf t-polyethylenimine (mPEG−PCL-g-PEI) polymer to form 150 nm drug-loaded micelles, with the intention that the grafted PEI would be efficacious against Candida biofilms. The micelles were freeze-dried and compressed into tablets with a range of excipients to slowly release the drug to treat local infections. The results were as expected, where the micellar encapsulation showed no improvement in AmB efficacy with planktonic cells; however, there was a significant enhancement of efficacy when studied with biofilms. This is critical, since biofilms are notoriously difficult to treat due to the poor transport properties associated with their polymeric matrix. It is becoming increasingly clear that new methods for the treatment of mycoses are critically necessary to improve upon human health and agricultural supply. There are very few examples where soft-matter plays a leading role in developing

sides of the lactone ring and amphoteric behavior due to the ionizable carboxyl and amine groups.49 Because AmB has poor skin permeability, it is not administered for transdermal applications. Furthermore, AmB exhibits poor solubility in aqueous media at physiological pH, as well as in many organic solvents.49,52 Highly acidic or basic pHs can promote solubility due to salt formation; however, these conditions also cause degradation of the drug. The salt form reduces the antimycotic activity rendering the drug useless for clinical applications.49,52 AmB binds to sterols in the cell-membrane with a preference toward ergosterol. However, it can also bind cholesterol of mammalian cells making it toxic, especially, to kidney cells, which are rich in cholesterol leading to nephrotoxicity.53 AmB destroys fungal cells by intercalating into the plasma cell membrane acting as a pore former, which impacts the Na+, K+, and H+ permeability as well as the loss of carbohydrates and proteins.49 The efficacy of AmB on an infection is strain dependent, as to whether the drug is a true fungicide or fungistatic agent. Due to the challenging physicochemical properties of AmB, several formulations exist on the market, including micellar dispersions, lipid complexes, liposomes, and colloidal dispersions with different efficacy/safety profiles.49 Fungizone is a micellar dispersion of AmB and sodium deoxycholate (1:2 molar ratio), also known as “conventional amphotericin”. Because of its 30 year history of broad-spectrum activity and low clinical resistance, it was considered the “firstline treatment” until lipid-based medicines (AmBisome, Abelcet, and Amphocil) were introduced in the 1990s, mitigating the adverse side-effects associated with Fungizone. Side effects associated with Fungizone include, but are not limited to, nephrotoxicity, azotemia, and hypocalcemia.49,54 Additionally, an optimal dosage of Fungizone remains to be determined and is therefore modified on a patient-by-patient basis.49 The lipid complexes have since supplanted Fungizone but come with similar, though less, pronounced side-effects. The current “first-line treatment” is liposomal AmB (Ambisome), which encapsulates 50 mg of AmB in small unilamellar vesicles (∼70 nm).55 This treatment is effective across a broad range of fungal infections, prophylaxis of transplant patients, and fibril neutropenic patients unresponsive to broad-spectrum antibiotics.49 Recent work has focused almost exclusively on delivery systems for AmB using polymer microencapsulation techniques. Ludwig et al. prepared AmB in PLGA nanoparticles of ∼100 nm size using nanoprecipiation methods.56 These particles were shown to be 2-fold more efficacious against Aspergillus infection in vivo, with significant declines in hemolytic activity. The authors speculate that the aggregation state of AmB was, in part, responsible for the decreased toxicity. H


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Figure 11. Synthesis and characterization of PEGylated nanoparticles. (A) Scheme for the functionalization of PAMAM G5.0 dendrimers; R = one G5 arm. (B) 1H NMR spectrum of PEGylated-PAMAM particles (D2O, 600 MHz, 512 scans). (C) DLS data confirming the size of the PEGylated nanoparticles in H2O before and after encapsulation with Pc 4. (D) Pc 4 dissolved in DMF (left) and water-solubilized Pc 4 encapsulated in PEGylated-PAMAM nanoparticles (right). Reproduced with permission from ref 70. Copyright 2017 American Chemical Society.

Hutnick et al. developed an encapsulation system for the phthalocyanine Pc 4, a proven PDT reagent that has seen success in clinical trials even given its poor pharmacokinetic properties (i.e., extremely poor water solubility).67−69 The researchers chose to use a PEGylated G5 PAMAM dendrimer to encapsulate the highly hydrophobic drug (Figure 11).70 This formulation was able to encapsulate a high concentration of Pc 4, while eliminating the need to solubilize the therapeutic in hepatotoxic organic solvents. Furthermore, the dendrimer formulation showed equal efficacy as a free drug when prepared in DMF when tested against resistant strains of C. albicans. The researchers further tried to target the nanoparticle by appending a chitin-binding peptide to the exterior of the dendrimer to bind to the cell wall of fungal cells. Unfortunately, this decreased the efficacy of the formulation, likely due to the hydrophobic collapse of the peptide component. Taken together, these results are a promising start to transitioning therapeutic molecules to the clinic that may not have optimal pharmacokinetic properties.

these tools. Two recent examples highlight where polymers could act as antifungals or as delivery systems for therapeutic agents that are still in development but face pharmacological challenges. One such example uses cationic nylon-3 polymers (also known as β-peptides) as the active agent.64 Low molecular weight polymers were synthesized by anionic ringopening polymerization of lactams to form amphiphilic and cationic polymers of ∼3.5 kDa (Figure 10). These molecules showed strong activity against Candida and Cryptococcus. Furthermore, there was a significant synergistic advantage for the treatment of fluconazole resistant strains of Aspergillus. The only downside to these molecules is the variable toxicity to human cells, with macrophages showing high lytic activity. With that being said, these molecules are in the early stages of development and with further optimization, could represent a new paradigm in antifungal treatments or in combination with established treatments. One final area where polymers will likely have an impact in antifungal drug delivery is in their use to improve the pharmacological properties of emerging therapeutics. One class of potential therapeutic molecules are agents used for photodynamic therapy (PDT) for localized infections.65,66 These molecules are of particular interest because resistance mechanisms have yet to be reported for microbial treatments. An emerging PDT class is that of phthalocyanine moieties that generate reactive oxygen species leading to apoptosis of cells in the immediate vicinity of the active PDT agent. Recently,

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CONCLUSIONS, CHALLENGES, AND FUTURE DIRECTIONS Nanoparticles are versatile materials for the development and delivery of better antimicrobial therapeutics. Their tunable functionality, multivalency, and architecture make them attractive candidates in the effort toward eradication of multidrug resistant microbes, as they are small enough to be I


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(8) Dehaini, D.; Fang, R. H.; Zhang, L. Biomimetic Strategies for Targeted Nanoparticle Delivery. Bioeng. Transl. Med. 2016, 1 (1), 30− 46. (9) Sharma, A.; Kumar Arya, D.; Dua, M.; Chhatwal, G. S.; Johri, A. K. Nano-Technology for Targeted Drug Delivery to Combat Antibiotic Resistance. Expert Opin. Drug Delivery 2012, 9 (11), 1325−1332. (10) Zhang, X.-Q.; Xu, X.; Bertrand, N.; Pridgen, E.; Swami, A.; Farokhzad, O. C. Interactions of Nanomaterials and Biological Systems: Implications to Personalized Nanomedicine. Adv. Drug Delivery Rev. 2012, 64 (13), 1363−1384. (11) Kamaly, N.; Yameen, B.; Wu, J.; Farokhzad, O. C. Degradable Controlled-Release Polymers and Polymeric Nanoparticles: Mechanisms of Controlling Drug Release. Chem. Rev. 2016, 116 (4), 2602− 2663. (12) Elnaggar, M. A.; Subbiah, R.; Han, D. K.; Joung, Y. K. LipidBased Carriers for Controlled Delivery of Nitric Oxide. Expert Opin. Drug Delivery 2017, 14 (12), 1341−1353. (13) Wo, Y.; Brisbois, E. J.; Bartlett, R. H.; Meyerhoff, M. E. Recent Advances in Thromboresistant and Antimicrobial Polymers for Biomedical Applications: Just Say Yes to Nitric Oxide (NO). Biomater. Sci. 2016, 4 (8), 1161−1183. (14) Schairer, D. O.; Chouake, J. S.; Nosanchuk, J. D.; Friedman, A. J. The Potential of Nitric Oxide Releasing Therapies as Antimicrobial Agents. Virulence 2012, 3 (3), 271−279. (15) Boucher, H. W.; Talbot, G. H.; Bradley, J. S.; Edwards, J. E.; Gilbert, D.; Rice, L. B.; Scheld, M.; Spellberg, B.; Bartlett, J. Bad Bugs, No Drugs: No ESKAPE! An Update from the Infectious Diseases Society of America. Clin. Infect. Dis. 2009, 48 (1), 1−12. (16) Santajit, S.; Indrawattana, N. Mechanisms of Antimicrobial Resistance in ESKAPE Pathogens. BioMed Res. Int. 2016, 2016, 2475067. (17) Webber, M. A. The Importance of Efflux Pumps in Bacterial Antibiotic Resistance. J. Antimicrob. Chemother. 2003, 51 (1), 9−11. (18) Fisher, J. F.; Mobashery, S. Enzymology of Bacterial Resistance. Reference Module in Chemistry, Molecular Sciences and Chemical Engineering 2010, 8, 443−487. (19) Sköld, O. Sulfonamide Resistance: Mechanisms and Trends. Drug Resist. Updates 2000, 3 (3), 155−160. (20) Lutgring, J. D.; Limbago, B. M. The Problem of Carbapenemase-Producing-Carbapenem-Resistant-Enterobacteriaceae Detection. J. Clin. Microbiol. 2016, 54 (3), 529−534. (21) Shaaban, M. I.; Shaker, M. A.; Mady, F. M. Imipenem/cilastatin Encapsulated Polymeric Nanoparticles for Destroying CarbapenemResistant Bacterial Isolates. J. Nanobiotechnol. 2017, 15 (1). DOI: 10.1186/s12951-017-0262-9 (22) Nguyen, T.-K.; Lam, S. J.; Ho, K. K. K.; Kumar, N.; Qiao, G. G.; Egan, S.; Boyer, C.; Wong, E. H. H. Rational Design of Single-Chain Polymeric Nanoparticles That Kill Planktonic and Biofilm Bacteria. ACS Infect. Dis. 2017, 3 (3), 237−248. (23) Namivandi-Zangeneh, R.; Kwan, R. J.; Nguyen, T.-K.; Yeow, J.; Byrne, F. L.; Oehlers, S. H.; Wong, E. H. H.; Boyer, C. The Effects of Polymer Topology and Chain Length on the Antimicrobial Activity and Hemocompatibility of Amphiphilic Ternary Copolymers. Polym. Chem. 2018, 9 (13), 1735−1744. (24) Judzewitsch, P. R.; Nguyen, T.-K.; Shanmugam, S.; Wong, E. H. H.; Boyer, C. Towards Sequence-Controlled Antimicrobial Polymers: Effect of Polymer Block Order on Antimicrobial Activity. Angew. Chem., Int. Ed. 2018, 57 (17), 4559−4564. (25) Andrews, S. C.; Robinson, A. K.; Rodríguez-Quiñones, F. Bacterial Iron Homeostasis. FEMS Microbiol. Rev. 2003, 27 (2−3), 215−237. (26) El-Gendy, N.; Qian, J.; Eshelman, K.; Rivera, M.; Berkland, C. Antibiotic Activity of Iron-Sequestering Polymers. Biomacromolecules 2015, 16 (5), 1480−1488. (27) Bae, Y. H.; Park, K. Targeted Drug Delivery to Tumors: Myths, Reality and Possibility. J. Controlled Release 2011, 153 (3), 198−205. (28) Wong, P. T.; Tang, S.; Tang, K.; Coulter, A.; Mukherjee, J.; Gam, K.; Baker, J. R.; Choi, S. K. A Lipopolysaccharide Binding

internalized by planktonic cells. As nanotechnology is ever developing so too are the designs implemented to attack these infections microorganisms. From the more simplistic designs, PEGylated vesicles promote water solubility to the complex targeted approaches, which utilize targeting molecules to bind specific motifs expressed on the cellular surface. Most recently, nanoparticles are being designed as higher ordered structures to mimic bacteriophages or envelop microbes as means of eradicating infections. These novel approaches are less likely to have resistance mechanisms developed against them because they destroy the cell membrane before the microbe has an opportunity to adapt. However, a lack of fundamental, biological, pharmacological, and in vivo studies must be addressed before these approaches can be implemented for systemic administration. To this end, a knowledge gap exists in using soft-matter to treat fungal and protozoan-derived infections despite being responsible for some of the most common nosocomial and lethal infections (i.e., candidiasis and malaria, respectively). Additionally, the studies in the literature focus on planktonic cells, whereas the most common and critical conditions present in the form of a biofilm are causing persistent infections. As nanotechnology evolves, continued improvements to antimicrobial delivery should bring about cost-effective therapeutics sensitive and selective for a myriad of diseases. In a post-antibiotic era, nanoparticles are a promising drug delivery and treatment modality for combating our most aggressive microbial infections.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Jonathan K. Pokorski: 0000-0001-5869-6942 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS J.K.P. and M.A.H. acknowledge funding from the National Institute of Health (5P30AR039750), NIAMS Core Center: Skin Diseases Research Center.

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REFERENCES

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