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Review Cite This: ACS Infect. Dis. XXXX, XXX, XXX−XXX

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Signed, Sealed, Delivered: Conjugate and Prodrug Strategies as Targeted Delivery Vectors for Antibiotics Ana V. Cheng† and William M. Wuest*,†,‡ †

Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, United States Emory Antibiotic Resistance Center, Emory School of Medicine, 201 Dowman Drive, Atlanta, Georgia 30322, United States

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ABSTRACT: Innate and developed resistance mechanisms of bacteria to antibiotics are obstacles in the design of novel drugs. However, antibacterial prodrugs and conjugates have shown promise in circumventing resistance and tolerance mechanisms via directed delivery of antibiotics to the site of infection or to specific species or strains of bacteria. The selective targeting and increased permeability and accumulation of these prodrugs not only improves efficacy over unmodified drugs but also reduces off-target effects, toxicity, and development of resistance. Herein, we discuss some of these methods, including sideromycins, antibody-directed prodrugs, cell penetrating peptide conjugates, and codrugs. KEYWORDS: oligopeptide, sideromycin, antibody−antibiotic conjugate, cell penetrating peptide, dendrimer, transferrin

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inding new and innovative methods to treat bacterial infections comes with many inherent challenges in addition to those presented by the evolution of resistance mechanisms. The ideal antibiotic is nontoxic to host cells, permeates bacterial cells easily, and accumulates at the site of infection at high concentrations. Narrow spectrum drugs are also advantageous, as they can limit resistance development and leave the host commensal microbiome undisturbed.1 However, various resistance mechanisms make pathogenic infections difficult to eradicate: Many bacteria respond to antibiotic pressure by decreasing expression of active transporters and porins2 and increasing expression of efflux pumps,3,4 making it difficult for drugs to infiltrate cells and achieve killing concentrations. Furthermore, several species of bacteria sequester themselves in human macrophages5 or in biofilms,6 leading to persistent infections, which are difficult to reach with traditional antimicrobials. These problems can be complicated or even impossible to address with simple small molecules. An emerging strategy to overcome these challenges is the employment of antibiotic conjugates. In this Review, we will focus on the application of sophisticated conjugate strategies to enhance antibacterial activity. The conjugates covered enable temporary masking of activity through a cleavable prodrug linkage, directed delivery of a drug through conjugation, improved pharmacokinetic and pharmacodynamic (PK/PD) profiles, or some combination of the three.

Figure 1. Standard prodrugs.

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STANDARD PRODRUGS By definition, a prodrug is an inactive compound that undergoes a chemical transformation in vivo to remove a covalently linked moiety and release the active form of the drug. Adrien Albert coined the term in 1958 in reference to drugs that had been © XXXX American Chemical Society

revealed as precursor compounds, such as phenacetin (the precursor to acetaminophen) and chloral hydrate (which is Received: January 15, 2019

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DOI: 10.1021/acsinfecdis.9b00019 ACS Infect. Dis. XXXX, XXX, XXX−XXX

ACS Infectious Diseases

Review

Figure 2. Codrugs. Sites of cleavage are marked in red.

drug to its eventual FDA approval in 2014.18 Other strategies for increased aqueous solubility include the addition of an ionizable amine,21,22 succinic acid,23 sugars,24 and polyethylene glycol25 and the transformation of sulfides to sulfoxides.26 These groups yield the active compounds upon O → N acyl migration,21 enzymatic ester23,27 or glycosidic hydrolysis,24 proteolytic cleavage,28 or reduction.26 Conversely, when the lipophilicity of a drug must be increased for improved passive permeability, hydrophobic promoieties that can be hydrolyzed by esterases or peptidases may be appended to polar or ionized groups.29,30 Commonly, alkyl and aryl esters15,31 or N-acylated groups32 are synthesized to this effect. These moieties can also aid in improving the metabolic stability of a drug,17 prolonging its duration of action,33 or transport across the blood−brain barrier.34 The principles of simple prodrug design described above have prompted the development of much more sophisticated antibiotic conjugates. In fact, many of the approaches described hereafter take advantage of similar mechanisms of linker cleavage (highlighted throughout): enzyme- or environmentpromoted drug release proves crucial to the success of many conjugates.

converted by alcohol dehydrogenase to trichloroethanol, a sedative) (Figure 1).7 Throughout history, several drugs have been discovered in their prodrug form and were only later realized to be a precursor to the active compound. For instance, Gerhard Domagk won a Nobel prize for the development of Prontosil (Figure 1), one of the earliest modern antibiotics.8 However, it was later identified as a precursor to the actual active compound, sulfanilamide, likely metabolized by azoreductases produced either in the liver or by gut microbiota.9 Today, prodrugs are used for the treatment of cancer,10−12 neurological13,14 and cardiovascular diseases,15,16 and bacterial infections. In the past decade, the US Food and Drug Administration (FDA) has approved 30 prodrugs, 10% of which are for antibacterial applications.17−19 Prodrug strategies have traditionally been applied to rescue prospective drugs with disfavorable PK/PD profiles;20 the interplay between the steric and electronic influences of a chemical structure and its PK/PD profiles is not always straightforward, so designing improved drug derivatives often becomes a juggling act guided by the chemical intuition of medicinal chemists. Additionally, the optimization process can involve years of modification after each round of in vitro or in vivo results. Prodrugs allow chemists to install a temporary moiety in a molecule, removable by enzymes or other environmental conditions, to address one of the PK/PD variables without affecting the activity and binding of the active compound, saving time and resources in the drug development process. Depending on the active molecule under investigation, it may be desirable to increase hydrophilicity or lipophilicity to improve solubility or passive permeability, respectively. The promoieties used in these situations tend to be small, simple in function, and relatively easy to introduce synthetically. For example, the addition of phosphate groups has greatly improved the aqueous solubility of several compounds; two of the three antibacterial prodrugs approved by the FDA in the past decade are phosphate esters. Ceftaroline fosamil (Figure 1) is an Nphosphono prodrug of the novel cefozopran derivative T-91825 for the treatment of methicillin-resistant Staphylococcus aureus (MRSA).17 The addition of an N-phosphono group, cleaved in the body by plasma phosphatases, boosted the solubility of their lead compound from 2.3 mg/mL to >100 mg/mL. Similarly, addition of a phosphate to tedizolid (Figure 1), an oxazolidinone antibiotic for the treatment of several Gram-positive infections, improved water solubility and facilitated the advancement of the

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CODRUGS Sometimes called mutual prodrugs, codrugs35 consist of two covalently linked entities whose cleavage releases two different active drugs. Codrugs benefit from improved PK/PD profiles in the same way that simple prodrugs do. Choosing the site of linkage on each compound carefully can mask labile groups, which are otherwise prone to degradation. They also enjoy advantages over joint administration of separate therapies. For instance, the type of linker allows control over the site of release and can confer additional metabolic stability. The intertwined PK/PD properties of the linked drugs ensure the equal dosing of the two entities for full utilization of their tandem or synergistic functions. Codrugs are an intriguing innovation, especially as combination therapies gain popularity. In addition to the benefits listed above, they have the potential to limit resistance development by inhibiting multiple targets. Unfortunately, their application is limited to compatible therapies, which benefit from release in the same environment. Additionally, they are mostly limited to 1:1 combinations, as it can become difficult to rationally link more than two drug units. Consequently, this limits combinations to drugs with similar potencies. There are B



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membranes and resultant internalization. Unfortunately, hydrolytic drug release yielded squalenic acid as a byproduct, leading to high toxicity. Abed et al. hypothesized that shorter terpenes would limit cytotoxicity and instead synthesized acid labile geranyl- and farnesyl-penicillin G (Figure 3).43 Indeed, the geranyl-penG prodrug showed decreased toxicity in murine macrophages (IC50 = 72.5 μg/mL) compared to the equivalent squalene conjugate (IC50 = 18 μg/mL). However, farnesyl-penG (IC50 = 22 μg/mL) displayed a similar profile to squalene.

limited examples of this technique, making codrugs a prime area for development. Codrugs were first introduced in 1980 with the development of a β-lactam/β-lactamase inhibitor (ampicillin/sulbactam) codrug, sultamicillin (Figure 2).36 Ampicillin and sulbactam are poorly absorbed when administered separately, but sultamicillin displayed fast absorption and enabled the joint and equal administration of a β-lactam and an inhibitor of its bacterial resistance mechanism. It also decreased diarrhea and dysentery, common side effects of the separately dosed drugs. Today, sultamicillin is prescribed for the treatment of a myriad of infections, including skin, respiratory, and urinary tract infections caused by S. aureus, Streptococcus pneumoniae, Escherichia coli, Klebsiella, and Enterobacter. Recently, Cacciatore et al. have investigated codrugs using the phenolic monoterpenoid antimicrobial carvacrol as one of the therapies (Figure 2).37 Known for its antifungal and antitumor activity, carvacrol also disrupts bacterial membranes. Through conjugation with various sulfur compounds via an enzymatically cleavable ester bond, antibacterial activity in S. aureus, Staphylococcus epidermidis, E. coli, and Pseudomonas aeruginosa, including some biofilm inhibition, was achieved. However, minimum inhibitory concentrations (MICs) were suboptimal, requiring further analog development. Ester-linked codrug strategies have also been applied to a fleroxacin-desacetylcefotaxime conjugate (Ro 23-9424)38 and a ciprofloxacindesacetylcefotaxime conjugate (Ro-24-6392),39 which both displayed broad antibacterial activity (Figure 2).

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DENDRIMERS Derived from the Greek word “dendron” for tree, dendrimers44,45 pose an extremely versatile macromolecular drug delivery system for hydrophobic small molecules or molecules that do not easily cross mammalian membranes. Mostly used in cancer treatment, they are branching structures composed of repeating units with many functionalizable sites. Dendrimers are named using several structural features: generations, core, and monomers, although sometimes the core is omitted. The number of generations refers to the number of layers radiating from the core, and the type of monomer used to build the branches determines the “family” in which the dendrimer belongs (Figure 4a). There are three methods commonly used to conjugate drugs to dendrimers: noncovalent micellar encapsulation,47 ionic coordination or chelation,48 and covalent prodrug attachment to the dendrimer edges (Figure 4a). While improved intracellular accumulation is useful in itself, dendrimers can also be polyconjugated to both drugs and targeting moieties, enabling the directed delivery of antibiotics. Kumar et al. accomplished this by noncovalently encapsulating rifampicin, a hydrophobic antitubercular drug with low macrophage penetration, in mannosylated dendrimers with five generations of polypropyleneimine branches building off an ethylene diamine core (G5 EDA-PPI) (Figure 4b).45 This strategy takes advantage of surface-bound mannose-binding proteins, which then facilitate receptor-mediated endocytosis. The conjugate experienced significantly increased concentrations of rifampicin in alveolar macrophages in comparison to free rifampicin, as well as superb drug release at pH 5.0 (pH of phagolysosomes). Additionally, researchers observed decreased toxicity in a Vero cell line. In another example of creative dendrimer engineering, a G5 poly(amidoamine) (PAMAM) dendrimer was covalently conjugated to photocaged ciprofloxacin and lipopolysaccharide (LPS)-binding groups (either polymyxin B or ethanolamine) (Figure 4c).46 The LPS-binding groups direct the conjugate to membranes of Gram-negative bacteria, and then, exposure to UVA light (365 nm) cleaves the photolabile ortho-nitrobenzyl linker between the dendrimer and ciprofloxacin. Although antibacterial activity was lower for the conjugate than for free ciprofloxacin, the lack of UV exposure had a limited effect on bacterial viability, validating the photocontrolled release of antibiotic. Dendrimers have been utilized in many antifungal, antiviral, and anticancer applications, such as a dual drug delivery dendrimer for leukemia.49 Inspiration can be taken from these innovations for the design of future antibacterial dendrimer conjugates.

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TERPENOYL NANOMEDICINES Although few examples exist, terpenoylation of antibiotics via pH-sensitive ester bonds takes advantage of the hydrophobic

Figure 3. Terpenoyl prodrugs. Cleavage site marked in red.

effect to induce self-assembly of drug nanoparticles. This strategy debuted in 2006 when squalene was used with the anticancer drug, gemcitabine.40 Squalene was later used in conjugation with penicillin G (penG) for improved targeting of intracellular S. aureus infections (Figure 3).41 Although S. aureus is typically an extracellular pathogen, some subpopulations are able to sequester themselves within phagolytic cells42 and use them as vehicles to spread infection throughout the body. By forming small colony variants and persisters, S. aureus can survive the hydrolytic enzymes that kill most bacteria in these phagolysosomes. Antibiotics cannot easily penetrate phagocytes and must be administered at unattainable concentrations to eradicate infection. The ∼140 nm nanoparticles created by Sémiramoth et al. were stable in water and decreased intracellular bacterial populations by 87%, compared to the 56% decrease accomplished by penG alone.41 Authors suggested the nanoparticles entered murine macrophages via both clathrin-dependent and independent endocytosis. Squalene is a precursor of sterols and can adopt a sterol-like conformation, perhaps also contributing to its interaction with mammalian

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CELL PENETRATING PEPTIDES Cell penetrating peptides (CPPs) are short 5−30 residue cationic, amphipathic, or hydrophobic peptides capable of infiltrating cells without lysing (unlike antimicrobial peptides), C



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Figure 4. Dendrimer antibiotic conjugates. (a) General dendrimer structure and conjugation methods. (b) G5 EDA-PPI dendrimer.45 (c) Gramnegative targeting G5 PAMAM dendrimer/ciprofloxacin prodrug.46

a noncleavable variant, demonstrated the need for drug release to realize full synergistic bacterial killing. Additionally, P14KanS caused significant reduction in S. aureus biofilms, intracellular S. aureus, and planktonic MRSA and methicillin-susceptible Staphylococcus aureus (MSSA) strains.55 Similarly, Li and co-workers were able improve the targeting of intracellular Salmonellae Typhimurium with marine antimicrobial peptide N6 by attaching a CPP (Tat11) via a cathepsin-cleavable linker.56 They also observed improved stability of the conjugate with C-terminal amidation of the antimicrobial peptide. The Kelley group used two peptides to achieve the killing of intracellular infection.57 Methotrexate was covalently affixed to a cationic delivery peptide to facilitate bacterial cell penetration. However, an additional anionic peptide, attached by a β-lactamase-cleavable cephalosporin linker, enabled endocytosis in host macrophages (Figure 5b). The delivery peptide−methotrexate hybrid (dpMtx) also served to temper the toxicity of methotrexate to murine macrophages and was able to eradicate intracelluluar Mycobacterium smegmatis while methotrexate alone was not.

making them especially useful for intracellular infections. First discovered in 1988,50 CPPs have been shown to smuggle various molecules into cells through either covalent linkage or electrostatic binding. These advances have opened the door to a variety of payload-delivering CPP applications, including the delivery of imaging agents,51 tumor therapies,52 and antibiotic prodrugs.53−57 However, they still display low cell specificity and are susceptible to proteases. Furthermore, to the best of our knowledge, little is known of resistance development to CPPs, which will inevitably be a hurdle in the advancement of these prodrugs. Using a previously developed CPP, P14LRR,53 to target intracellular bacteria (discussed in the previous section), the Seleem group created a disulfide-linked P14LRR-kanamycin prodrug conjugate,54 dubbed P14KanS (Figure 5a). The proline-rich CPP adopts a helical conformation, and added cationic and hydrophobic character from guanidino and isobutyl groups enables it to penetrate mammalian membranes without lysing, reaching intracellular bacterial infections. P14KanS was designed to be cleaved in the reducing environment of mammalian cells to release P14LRR and kanamycin, both of which have antimicrobial activity. Thus, P14KanS may also be classified as a codrug. Clearance of macrophage-inhabiting Mycobacterium tuberculosis, Salmonella enteritidis, and Brucella abortus was observed in addition to reduction of Salmonella in an in vivo Caenorhabditis elegans model. A comparison to P14KanC,

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OLIGOPEPTIDES Membrane-bound oligopeptide permeases58−60 facilitate the uptake of a wide range of 2−8 length L-amino acid residues from the environment. As a result, bacteria have cleverly taken advantage of this active transport by synthesizing and excreting D



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Figure 5. Cell penetrating peptide conjugates. (a) P14KanS. (b) Double peptide methotrexate prodrug.

Figure 6. Oligopeptide prodrugs. (a) Natural oligopeptide prodrugs. (b) Synthetic oligopeptide prodrugs.

glucosamine 6-phosphate synthase. Bacilysin is produced by Bacillus subtilis and displays activity in many bacteria and fungi. Another B. subtilis oligopeptide, Rhizocticin A, and Streptomyces plumbeus’ Plumbemycin A are both phosphonooligopeptides with a C-terminal (Z)-L-2-amino-5-phosphono-3pentenoic acid (APPA) moiety.62 APPA is an irreversible inhibitor of threonine synthase, an enzyme critical to bacteria, plants, and fungi but not found in humans. Once internalized, these oligopeptides are hydrolyzed by peptidases to release active (S,Z)-APPA. Other natural oligopeptide drugs include alafosfalin63 (prodrug, cell wall synthesis inhibitor) and

small antibacterial molecules linked to short peptides that are transported by the permeases of other species and then typically (but not always) hydrolyzed by intracellular peptidases to release the active drug. Unfortunately, resistance to these prodrugs is quickly developed as the permeases are not essential to survival. A multitude of naturally occurring oligopeptide−antibiotic conjugates (Figure 6a) have been discovered and studied, such as bacilysin,61 a simple dipeptide prodrug with an N-terminal Lalanine linked to L-anticapsin, a nonproteinogenic amino acid that functions as an analog of glutamine to covalently inhibit E



Review

Figure 7. Sideromycins. (a) Natural sideromycins. (b) Biscatecholate siderophore−oxazolidinone prodrug.82 (c) Enterobactin−ciprofloxacin prodrug.83

Figure 8. Siderophore ligands. (a) Three main classes of siderophore ligands. (b) Mixed ligand β-lactam sideromycin.

tabtoxin64 (prodrug, glutamine synthetase inhibitor), among others. Utilization of active transport of oligopeptides has also inspired synthetic conjugates (Figure 6b). As early as 1989, diand tripeptide conjugates of sulfanilic acid were synthesized to increase its permeation into E. coli, resulting in a 207-fold enhancement in activity.65 More recently, Bartee et al. identified

potent inhibitors of 1-deoxy-D-xylulose-5-phosphate synthase. However, their use was hindered by low bacterial cell uptake. By synthesizing a peptidic enamide-alkyl acetylphosphonate prodrug, they achieved an impressive 2000-fold activity increase in E. coli.66 These results are a testament to the power of antibiotic conjugates to improve in vivo activity of small molecules. F



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Figure 9. Antibody−antibiotic conjugates. (a) Mechanism of AAC action in intracellular bacterial infections. (b) Cathepsin-cleavable AAC linker.101

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>125-fold improvement in MIC (0.4 μM) over oxazolidinone alone (>50 μM) when evaluated against β-lactamase-expressing Acinetobacter baumannii. These results are especially impressive because oxazolidinones cannot typically permeate the outer membranes of Gram-negative cells to reach their ribosomal target, limiting their activity to Gram-positive species. Additionally, β-lactamase dependence confers extra selectivity for drug-resistant targets. For even more specific intracellular release, Neumann et al. designed an enterobactin−ciprofloxacin conjugate (Figure 7c) selectively hydrolyzed by certain pathogenic strains of E. coli.83 This prodrug is not activated by the common enterobactin hydrolase, Fes, but instead by the pathogenic strain-associated hydrolase IroD. Specific linkers like those above enable selective targeting of resistant and pathogenic strains using broad-spectrum drugs. Typical siderophores are split into three main classes according to their iron-binding motifs: catecholates, hydroxamates, or α-hydroxy carboxylates (Figure 8a). Mixed ligand siderophores can be recognized by multiple receptors, mitigating the risk of resistance development. The Miller group has demonstrated that mixed ligand biscatecholate− monohydroxamate antibiotic conjugates (Figure 8b) had comparable or better MICs than single-type ligands.72,84,85 Although these conjugates were not prodrugs, as many β-lactam drugs do not require cleavage for antibacterial activity,79 they present an interesting future avenue for sideromycin exploration.86 Further, artificial siderophores (“sideromimics”) have been synthesized in nonlabile conjugation with monocarbams,87 sulfactams,88 monobactams,89 and lactivicin.90

SIDEROMYCINS Living organisms require iron to serve as an agent in redox metabolic pathways; however, bacteria often inhabit environments that are especially iron poor. To obtain iron, they biosynthesize and secrete small iron-chelating compounds (siderophores)67 to retrieve Fe3+ from their surroundings and return it to the cell.68 The iron-bound siderophores are recognized by membrane-bound receptors and then imported by active transporters. For a competitive advantage, bacteria also express receptors for siderophores produced by other microorganisms (xenosiderophores).69 In response to this “theft,” some microbes have evolved to excrete siderophore-linked antibiotics called sideromycins, which competitors unwittingly import, causing cell death.70,71 Although resistance may develop through mutations in siderophore receptors, it comes at a significant fitness cost, as bacteria with deficient siderophore uptake pathways suffer iron starvation.72 Inspired by this strategy, researchers have developed synthetic “Trojan horse” drugs73 to counter resistance mechanisms that decrease antibiotic uptake. Because mammals do not use siderophores, these prodrug conjugates selectively target bacteria. Further, species-specific siderophores may confer an added level of selectivity.74 Albomycins (Figure 7a) are naturally occurring sideromycins comprised of a ferrichrome-like siderophore covalently linked via a hydrolyzable serine to a thioribosyl pyrimidine antibiotic. Upon cleavage by bacterial peptidase N, the antibiotic inhibits transfer ribonucleic acid (tRNA) synthetase.70 Deletion of either the uptake machinery or hydrolytic enzyme results in resistance to albomycin.75 Isolated from Streptomyces sp., they have shown activity against Enterobacteriaceae, S. aureus, and S. pneumoniae.76 Another class of natural sideromycins, the salmycins (Figure 7a), were isolated from Streptomyces violaceus in 1995.77 These conjugates kill Staphylococci and Streptococci through the release of an aminoglycoside antibiotic. The investigation of synthetic siderophore−antibiotic conjugates with cytoplasmic targets has demonstrated the necessity of drug cleavage for full antibacterial activity,78,79 leading to the employment of various linkers. Some favorable results have been obtained using esterase-cleavable thiol-maleimide80 and “trimethyl-lock”-based linkers.81 However, these may still be activated by acid or extracellular esterases before entering the target bacteria. Recently, Liu et al. designed a siderophore− cephalosporin−oxazolidinone conjugate that addresses this issue (Figure 7b).82 By utilizing a covalent cephalosporin linker that can be cleaved by periplasmic β-lactamases, they achieved a

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TRANSFERRINS Transferrins (Tfs) are glycoproteins involved in the transport and sequestration of iron found in vertebrates. They can exhibit bacteriostatic activity due to iron chelation, which withholds essential iron from growing bacteria.91 However, bacterial transferrin binding protein A (TbpA) recognizes Tf and actively removes and internalizes its iron. As it turns out, Tf and TbpA have a long history of competitive evolution as detailed in a review by Barber and Elde.92 Nonetheless, researchers have used TbpA to their advantage by using Tfs as drug carriers through either covalent linkage or encapsulation of hydrophobic and aromatic small molecules. However, it is important to note that, without protein engineering, covalent linkage runs the risk of attaching antibiotic to a position important for Tf−receptor interaction. Additionally, Tfs are useful for the treatment of G



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Table 1. Miscellaneous Prodrugs and Conjugates

intracellular infections93 since host cells perform Tf−receptormediated endocytosis.94 Sulfonamides, some of the earliest antibiotics, target dihydrofolate reductase. Unfortunately, they are poorly soluble and highly toxic with painful side effects such as kidney stones,

limiting their usefulness. Triclosan is similarly restricted. However, noncovalent complexation of these antibiotics with ovotransferrin (OTf, found in bird and reptile eggs), achieved through incubation of OTf in excess antibiotic over 24 h, improved activity against various bacteria, including E. coli, H



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MISCELLANEOUS PRODRUGS AND DELIVERY STRATEGIES Many other novel conjugates and prodrug methods have been explored, including several that do not fit the categories described thus far or have not yet been applied to antibacterials. So as not to omit these innovations and to provide inspiration for future drug delivery development, we have summarized them in Table 1.

P. aeruginosa, S. epidermidis, S. aureus, Neisseria mucosa, and some intracellular infections.95 OTf alone lacked activity at equivalent concentrations to the antibiotic−OTf complexes, indicating that the antibiotics are internalized by the bacteria separate from OTf, possibly through a similar mechanism as Tf’s native substrate, iron. An analogous approach was used to tackle Chlamydia trachomatis, an obligate intracellular pathogen responsible for sexually transmitted infections. This bacterium’s clever life cycle permits it to reproduce only in vacuoles within host cells, while it exists as a metabolically inert form when traveling from cell to cell. Thus, the metabolically active form of C. trachomatis is shielded within a vacuole inside host cells, requiring antibiotics with exceptional cell penetration ability. Hai et al. addressed this with a covalent serum Tf−amoxicillin conjugate.93 Coupling was confirmed with mass spectrometry, which indicated the presence of one antibiotic per Tf. The resulting conjugate was significantly more effective than amoxicillin against intracellular C. trachomatis infections.

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CONCLUSIONS Antibiotic prodrugs and conjugates aid in addressing difficult-totreat bacterial infections, such as intracellular and persistent infections. By carefully choosing a linker or a directing moiety to build an antibiotic prodrug or conjugate, it is possible to induce site-specific release of active drug and/or improved accumulation at the site of infection, opening doors to many would-lead compounds suffering from PK/PD limitations or lack of specificity. In doing so, we can also limit off-target effects and toxicity or expand the spectrum of activity of known drugs. Although some of the described strategies have been used for several decades and are popular in anticancer, antiviral, and antifungal therapies, their employment in antibiotics is less extensive but promising. Prodrugs and directing strategies pose a supplementary strategy for addressing the increasingly urgent issue of antibiotic resistance. We can take inspiration from existing approaches and apply them to bacteria-specific receptors and active transport. Combined with the constant search for new antibiotics, this research will expand our repertoire of antibacterial therapies.

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ANTIBODY-DIRECTED PRODRUGS By directing broad-spectrum drugs to antigen-possessing species, antibody−antibiotic conjugates (AACs) have the potential to avoid unnecessary killing of commensal bacteria. These conjugates have also proven useful in the treatment of intracellular infections (Figure 9a). Although there are few examples of antibody−antibiotic prodrugs, there has been study of the site-dependent stability of antibody-linker linkage,96,97 and novel linkers are in development.98−100 In 2015, a group at Genentech successfully applied an antibody−antibiotic conjugate (AAC) prodrug to the treatment of intracellular S. aureus in mice,101 which has now completed phase I clinical trials. Lehar et al. administered vancomycin, daptomycin, linezolid, and rifampicin and, although these drugs handily defeated extracellular MRSA, they were unable to treat murine macrophage intracellular bacteria even at the maximum serum concentration.101 However, application of an optimized AAC prodrug composed of THIOMAB (an anti-S. aureus antibody) covalently tethered via a cathepsin-cleavable linker (Figure 9b) to rifampicin decreased amounts of MRSA in murine macrophages to below the detectable limit. While rifampicin cannot penetrate the membranes of macrophages due to insufficient lipophilicity, the AAC can easily accumulate at killing concentrations. It has been suggested that this approach could also be applied to M. tuberculosis infections.102 In another antibody-based approach, the use of photodynamic therapy to target P. aeruginosa was preliminarily investigated.103 The conjugate is composed of an antibody linked via an ethylenediamine spacer to several photosensitizers which, upon irradiation with light, release singlet oxygen and trigger death in nearby cells. Despite being highly reactive, singlet oxygen has a short lifetime that limits its activity to an area within 1000 Å of its generation, and the use of an antibody directs the formation of this unstable species to the site of infection. The conjugates were stable both in vitro and in an in vivo rat thigh abscess model. However, bacterial killing required saturated concentrations of conjugate due to the difficulty of lysing cells with thick cell walls. Another in vivo study of a different photosensitizer immunoconjugate demonstrated 75% killing of P. aeruginosa in mice,104 and two additional antibody− photosensitizer conjugates have since been tested.105,106

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

William M. Wuest: 0000-0002-5198-7744 Author Contributions

A.V.C. conceptualized the manuscript. A.V.C. and W.M.W. wrote the manuscript. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge funding from the National Institute of General Medical Sciences (GM119426), National Science Foundation (CHE1755698), and the Georgia Research Alliance based in Atlanta, Georgia. We also would like to thank Dr. William Shafer, Dr. Justin Shapiro, Dr. Taylor Hari, and Dr. Colleen Keohane for their feedback on the manuscript.

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ABBREVIATIONS AAC, antibody−antibiotic conjugate; AMP, antimicrobial peptide; CPP, cell penetrating peptide; EDA, ethylene diamine; FDA, US Food and Drug Administration; LPS, lipopolysaccharide; MIC, minimum inhibitory concentration; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillinsusceptible Staphylococcus aureus; OTf, ovotransferrin; PAMAM, poly(amidoamine); PD, pharmacodynamic; penG, penicillin G; PK, pharmacokinetic; PPI, polypropyleneimine; TbpA, transferrin binding protein A; Tf, transferrin; tRNA, transfer ribonucleic acid; UV, ultraviolet I



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