Peptide Amphiphiles with Distinct Supramolecular Nanostructures for

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Peptide Amphiphiles with Distinct Supramolecular Nanostructures for Controlled Antibacterial Activities Ruilian Qi, Pengbo Zhang, Jian Liu, Lingyun Zhou, Chengcheng Zhou, Na Zhang, Yuchun Han, Shu Wang, and Yilin Wang ACS Appl. Bio Mater., Just Accepted Manuscript • DOI: 10.1021/acsabm.8b00005 • Publication Date (Web): 30 May 2018 Downloaded from http://pubs.acs.org on May 30, 2018

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ACS Applied Bio Materials

Peptide Amphiphiles with Distinct Supramolecular Nanostructures for Controlled Antibacterial Activities †

†

†

Ruilian Qi, ,‡ Pengbo Zhang,§,‡ Jian Liu,ǁ,‡ Lingyun Zhou,§,‡ Chengcheng Zhou, Na Zhang, ,‡ Yuchun Han,*,† Shu Wang,*,§,‡ and Yilin Wang*,†,‡ †

Key Laboratory of Colloid, Interface and Chemical Thermodynamics, §Key Laboratory of

Organic Solids, and ǁKey Laboratory of Molecular Nanostructure and Nanotechnology, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. China ‡

University of Chinese Academy of Sciences, Beijing 100049, P. R. China

KEYWORDS Peptide amphiphile, lysine, antibacterial activity, aggregate CORRESPONDING AUTHOR *[email protected]; *[email protected]; *[email protected]

ACS Paragon Plus Environment

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ABSTRACT

Gemini-type peptide amphiphiles 12-(Lys)n-12 (n = 2, 4, and 6) with different lysine spacer lengths have been established and exhibit excellent antibacterial activities. By varying the lysine number in the spacer, the distinct aggregates with zero ∼ three dimentional structures (fibers, short rods and spherical aggregates) are formed. These different length/diameter ratios of aggregates have great effects on the antibacterial activities and cytotoxicity. 12-(Lys)2-12 has a relatively higher MIC value and shows toxicity toward mammalian cells just above its MIC value, while 12-(Lys)4-12 and 12-(Lys)6-12 have lower MIC values and no cytotoxicity even at 5 times MIC values.


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Bacterial resistance has been a global health problem due to the indiscriminate use of antibiotics and the subsequent creation of bacteria that can survive traditional treatment.1-3 To address the challenges associated with bacterial resistance, scientists have made great efforts to develop novel antibacterial agents4-12. Antimicrobial peptides (AMPs), also called host defense peptides (HDPs), are endogenous components of the innate immune response found among all classes of life. Because of their broad spectrum of activity, lower levels of bacterial resistance, and the speed of their action on pathogens, AMPs have been recognized as a potential candidate for next generation of antibacterial agents.5 However, some drawbacks, including poor bioavailability, high production cost, and non-specific toxicity against mammalian cells, limit their wide applications.13 An important area of AMPs research is the exploration and development of chemical mimics of natural peptides. It is hoped that the novel synthetic AMPs would overcome the challenges currently faced with natural AMPs. Positive charge and hydrophobicity are considered essential for AMP functions even though the mode of action is still elusive. Cationic charges are helpful for the peptides to bind with the negatively charged bacterial membranes, and hydrophobic moieties of peptides possibly provide lipophilic anchors that eventually cause membrane disruption.6-8 In addition, a common feature of the AMPs is that they all have an amphipathic structure.14-15 Due to combing the above structure characters of AMPs, peptide amphiphiles (PAs) are expected to be the efficient antibacterial agents.16-17 Up to now, the studies on antibacterial aspect of PAs are relatively rare, especially the gemini-type PAs have not been explored. It is well known that PAs can self-assemble into multifarious supramolecular nanostructures with shape diversities ranging from spheres to cylinders, twisted ribbons, belts, and tubes.18-19 Researchers have found that the aggregate structures play critical roles in cellular uptake and


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circulation time.20-22 But the correlation between these ordered structures and antibacterial activities is largely absent.23-24 To know the effect of different aggregate structures on the antibacterial activity will help to understand the antibacterial mechanism, thus facilitating to establish high-efficient PA antibacterial agents. In this work, by establishing three novel geminitype PAs 12-(Lys)n-12 (n = 2, 4, and 6) with different lysine spacer lengths, we successfully construct the distinct aggregates, and observe they have different antibacterial activities and action mechanisms to the bacteria (Scheme 1). Scheme 1. Schematic graph of antibacterial mechanism of peptide amphiphiles 12-(Lys)n-12 with varying backbone chain lengths (n = 2, 4, 6).

Three gemini-type PAs 12-(Lys)n-12 (n = 2, 4, and 6) were synthesized through solid method and purified by high-performance liquid chromatography (Figures S1, S3 and S5). Their chemical structures were characterized by 1H NMR and mass spectra (Figures S2, S4 and S6). On one hand, the typical basic amino acid lysine, frequently existed in natural AMPs,25 is selected as the positive charged spacer of gemini-type PAs. The number of lysine in the spacers


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for PAs 12-(Lys)n-12 is 2, 4 and 6, respectively. The change of lysine number would affect the hydrogen bonding and electrostatic forces between the headgroups, which may lead to forming different aggregate structures. It is noted to us that the short peptides in the present study are more easily obtained relative to natural AMPs which in general contain 10 to 50 amino acids.5 On the other hand, the double alkyl chains are used as the hydrophobic parts of the gemini-type PAs, which makes the PA have strong aggregation ability and high-efficient functions.26-27 Moreover, the alkyl chain can easily permeate the biological membrane due to having similar structure to lipid hydrophobic part. Gram-negative E. coli is selected to evaluate the antibacterial activities of these gemini-type 12-(Lys)n-12 PAs. The protection from the double layer membrane, especially outer membrane, makes Gram-negative bacteria more difficult to kill than Gram-positive ones,28 and half of the infections are originated from Gram-negative E. coli.29 The present results show that these 12(Lys)n-12 PAs exhibit excellent antibacterial activities against E. coli. And the antibacterial abilities are related to the structures of the aggregates formed by 12-(Lys)n-12 PAs. The three 12(Lys)n-12 PAs have very strong self-assembly abilities, with remarkably low critical aggregate concentrations (CACs) which fall between 0.68 and 3.50 µM measured by surface tension methods (Figure 1b and Table 1). Although only differing in the lysine spacer lengths, these three 12-(Lys)n-12 PAs form the distinct aggregate structures, as observed by size and morphology measurements (Figure 1a). 12-(Lys)2-12 forms fibers of high length/diameter ratio with size up to micrometers, while 12-(Lys)4-12 and 12-(Lys)6-12 separately aggregate into rods and spherical aggregates of low length/diameter ratio, with the size of 100 ~ 300 nm. When added into E. coli, these gemini-type 12-(Lys)n-12 PAs greatly decrease the viability of E. coli and their antibacterial activities increase with concentration (Figure 1c). The antibacterial


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activities are reported as minimal inhibitory concentration (MIC) values, determined by sigmoidal fits of dose–response data (Figure 1d). The MIC values against E. coli are 27.0, 6.4, and 7.5 µM for 12-(Lys)2-12, 12-(Lys)4-12 and 12-(Lys)6-12, respectively (Table 1). These values are obviously larger than their respective CACs, showing the antibacterial activities come from the formed aggregates. Compared with 12-(Lys)2-12, 12-(Lys)4-12 and 12-(Lys)6-12 are more effective, possibly due to forming relative small and low length/diameter ratio of aggregates. Therefore, the antibacterial abilities strongly depend on the lysine spacer length and resulting aggregate structures.

Figure 1. (a) Cryo-TEM images of 50.0 µM 12-(Lys)2-12, 20.0 µM 12-(Lys)4-12 and 50.0 µM 12-(Lys)6-12. The insets are the corresponding size distributions measured by DLS. (b) Surface tension curves of 12-(Lys)n-12. (c) Number of colony forming units (CFU) of E. coli before (control) and after adding 12-(Lys)n-12 on LB agar plate. (d) Antibacterial activity of 12-(Lys)n12 toward E. coli, where error bars represent standard deviations of data for three separate measurements.


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Table 1. Critical aggregate concentration (CAC), minimal inhibitory concentration (MIC) values against E. Coli, half maximal inhibitory concentration (IC50) values of 12-(Lys)n-12, and thermodynamic parameters of the binding between 12-(Lys)n-12 and E. coli derived from ITC curves. CAC (µM)

MIC (µM)

N (×107)

Kb (×105)

IC50 (µM)

12-(Lys)2-12

2.50

27.0

1.93

2.33

> 16.0

12-(Lys)4-12

0.68

6.4

11.91

6.90

> 32.0

12-(Lys)6-12

3.50

7.5

0.49

1.32

> 32.0

To gain visual insights into the correlation between antibacterial activity and aggregate structure, the morphological changes of E. coli in response to exposure to the different 12-(Lys)n12 aggregates were observed by scanning electron microscopy (SEM) (Figure 2a). For the control group without adding 12-(Lys)n-12, the clear edges and surface integrity of bacterial cells are presented. After adding 12-(Lys)2-12 solutions, the long fibers formed by 12-(Lys)2-12 bind to the bacterial surface and induce bacterial clustering. The induced bacterial aggregation can inhibit the microbial growth.23, 30 Different from 12-(Lys)2-12, the collapsed, split, and merged membranes are seen when E. coli are treated with 12-(Lys)4-12 and 12-(Lys)6-12. The bacterial membrane damage caused by these PAs was also investigated by using BacLight Live/Dead viability kit to stain bacteria for CLSM. The kit contains two fluorescent dyes: SYTO9 penetrates both live and dead bacteria, whereas propidium iodide (PI) penetrates bacteria with damaged membranes and quenches the fluorescence of SYTO9.31 E. coli in the control group has intact membranes, so they can be stained by SYTO9 and fluoresce green (Figure 2b). After


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treatment by three 12-(Lys)n-12, most of E. coli are stained by PI and fluoresce red, indicating the membranes are damaged. Consistent with the SEM results, the obvious aggregation of E. coli induced by 12-(Lys)2-12 is observed, which is distinct from the other two PAs. Therefore, it can be concluded that all 12-(Lys)n-12 aggregates target at the bacterial cell membrane. However, their interaction modes with bacteria are different. 12-(Lys)2-12 fibers mainly absorb on the bacterial surface and induce the aggregation of bacteria, thus less 12-(Lys)2-12 molecules are used to lysis the membrane, resulting in a relatively high MIC value. While small aggregates formed by 12-(Lys)4-12 and 12-(Lys)6-12 will easily disrupt the bacterial membrane, which contributes to their very low MIC values.

Figure 2. (a) SEM images of E. coli (b) CLSM images of E. coli stained by PI & SYTO9 before incubation and after incubation with 12-(Lys)n-12 solutions at their MICs. (c) Zeta potential results of E. coli upon adding different concentrations of 12-(Lys)n-12 solutions. (d) Raw calorimetric titration curve of titrating 12-(Lys)4-12 solution into E. coli solution, which shows


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the variations of heat flow P as a function of time. Observed enthalpy changes against the 12(Lys)4-12/E. coli molar ratios. To further study the interactions between different aggregate structures and E.coli, zeta potential measurements were performed to investigate the potential change of E. coli before and after treatment by three 12-(Lys)n-12 PAs. As shown in Figure 2c, the potentials of E. coli exhibit obvious positive shift from -53.8 ± 1.2 mV to -38.3 ± 0.7 mV with the addition of 12(Lys)2-12, while the potentials of E. coli do not change distinctly with the addition of 12-(Lys)412 or 12-(Lys)6-12. Previous studies have shown that inserting into the membrane by hydrophobic interactions does not affect the zeta potential of bacteria, but binding to the bacterial surface by electrostatic interactions leads to a remarkable positive potential shift.32 That is, 12(Lys)2-12 fibers mainly electrostatically bind to the surface of the bacteria membranes, while most of small aggregates formed by 12-(Lys)4-12 or 12-(Lys)6-12 can further insert into lipid domain of the membrane after their electrostatically binding with the bacteria membranes. The corresponding thermodynamic changes in the binding process of E. coli with these 12- (Lys)n-12 PAs were investigated by isothermal titration calorimetry (ITC) (Figure 2d and Figure S7). Taking 12-(Lys)4-12 as a representative, the raw calorimetric titration curve and observed enthalpy change curve of titrating 12-(Lys)4-12 solution into E. coli solution are shown in Figure 2d. With the addition of 12-(Lys)4-12, the observed enthalpy changes (∆Hobs) are initially exothermic due to 12-(Lys)4-12 electrostatically binding with E. coli. Then the ∆Hobs values become less negative, which is derived from the decrease of electrostatic binding and PA inserting into lipid domain by hydrophobic interaction. Finally, ∆Hobs approaches zero, suggesting that the binding with E. coli reaches the saturation. The derived binding numbers (N) of these PAs with per E. coli as well as the corresponding binding constants (K) are listed in


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Table 1. The binding number N decreases in the following order: 12-(Lys)4-12 > 12-(Lys)2-12 > 12-(Lys)6-12, and the same change is observed in binding constant K. This can be explained by the electrostatic interaction and hydrophobic interaction between these 12-(Lys)n-12 PAs and E. coli. The highly charged fibers formed by 12-(Lys)2-12 endow it strongest electrostatic interaction with E. coli, but limit its inserting into lipid domain by hydrophobic interaction. Both 12-(Lys)4-12 and 12-(Lys)6-12 can insert into bacterial membrane, but the hydrophobic interaction with membrane is weaker for more positively charged 12-(Lys)6-12. The optimal balance between electrostatic interaction and hydrophobic interaction makes 12-(Lys)4-12 have strongest interaction with E. coli. To sum up, the stronger electrostatic interaction between 12(Lys)2-12 fibers with E. coli makes them mainly bind to the membrane surface. While the relatively weaker electrostatic interaction between small aggregates formed by 12-(Lys)4-12 or 12-(Lys)6-12 with E. coli allows them further inserting into membrane by hydrophobic interaction. An important requirement for the biomedical applications of the antibacterial agents is that they exhibit excellent antibacterial activity but low cytotoxicity. Therefore, the toxicity of these gemini-type PAs toward mammalian cells (HaCat) was tested by the MTT assay. The half maximal inhibitory concentration (IC50) values of these 12-(Lys)n-12 PAs are summarized in Table 1. As shown in Figure 3, 12-(Lys)2-12 (MIC = 27.0 µM) has no cytotoxicity at 8.0 µM, but has obvious cytotoxicity at 32.0 µM. For 12-(Lys)4-12 (MIC = 6.4 µM) and 12-(Lys)6-12 (MIC = 7.5 µM), they do not exhibit cytotoxicity at both 8.0 and 32.0 µM (five times MIC values). That is to say, 12-(Lys)2-12 has non-selective toxicity against E. coli and mammalian cells, while 12-(Lys)4-12 and 12-(Lys)6-12 can selectively kill E. coli. This is because 12-(Lys)412 and 12-(Lys)6-12 have stronger electrostatic interaction with E. coli which carries more


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negative charges than mammalian cells. The high cytotoxicity of 12-(Lys)2-12 may be due to the fact that 12-(Lys)2-12 fibers carry more positive charges than small aggregates formed by 12(Lys)4-12 and 12-(Lys)6-12 (Figure S8). Highly charged 12-(Lys)2-12 fibers make them still have strong electrostatic interaction with mammalian cells.

Figure 3. (a) Cell viability of HaCaT cells after incubation with the aqueous solutions of 12(Lys)n-12 (n = 2, 4, 6) at different concentrations. (b) The effects of lysine length (2, 4, 6) on the viability of HaCat cell and E. coli in the presence of 8.0 and 32.0 µM 12-(Lys)n-12 solutions. In summary, three gemini-type PAs 12-(Lys)n-12 with different lysine spacer lengths, which can self-assemble into different aggregates at remarkably low concentrations, have been developed and they display excellent antibacterial activities. A direct correlation between the aggregate structures and antibacterial activities has been established. Highly charged fibers formed by 12-(Lys)2-12 mainly electrostatically bind to E. coli membrane and less 12-(Lys)2-12


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molecules can insert into lipid domain, which makes it less efficient in killing bacteria. Small aggregates (short rods and spherical aggregates) formed by 12-(Lys)4-12 and 12-(Lys)6-12 can easily insert into membrane through hydrophobic interaction and destroy the membrane, which makes them more efficient in killing bacteria. The aggregate structures also have great effects on the cytotoxicity of these 12-(Lys)n-12 PAs. Highly charged 12-(Lys)2-12 fibers have high toxicity against mammalian cells at its MIC value, while small aggregates formed by 12-(Lys)412 and 12-(Lys)6-12 have no toxicity toward mammalian cells even at 5 times MIC values. This work will help to understand the relationship between self-assembly structures and antibacterial activities, and also shed new insights on how to design high-efficient antibacterial agents.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Experimental procedures, characterization data, ITC titration data, zeta potential results of gemini-type PAs. (PDF)

AUTHOR INFORMATION Corresponding Author *[email protected] *[email protected] *[email protected] Notes


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The authors declare no competing financial interests. ACKNOWLEDGMENT We are grateful for financial support from the National Natural Science Foundation of China (21761142007, 21773261, 91527306). We are thankful to Dr. Dong Wang, Dr. Meiwen Cao and Prof. Hai Xu, from Centre for Bioengineering and Biotechnology, China University of Petroleum (East China), for their generous help during cryo-TEM experiments. REFERENCES (1)

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Peptide Amphiphiles with Distinct Supramolecular Nanostructures for

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