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. 2022 Dec 8;65(23):15819-15839.
doi: 10.1021/acs.jmedchem.2c01469. Epub 2022 Nov 28.

Membrane-Active Cyclic Amphiphilic Peptides: Broad-Spectrum Antibacterial Activity Alone and in Combination with Antibiotics

Eman H M Mohammed  1   2   3 , Sandeep Lohan  1   3 , Tarra Ghaffari  1 , Shilpi Gupta  1 , Rakesh K Tiwari  1 , Keykavous Parang  1
Affiliations

Membrane-Active Cyclic Amphiphilic Peptides: Broad-Spectrum Antibacterial Activity Alone and in Combination with Antibiotics

Eman H M Mohammed et al. J Med Chem. .

Abstract

We designed a library of 24 cyclic peptides containing arginine (R) and tryptophan (W) residues in a sequential manner [RnWn] (n = 2-7) to study the impact of the hydrophilic/hydrophobic ratio, charge, and ring size on the antibacterial activity against Gram-positive and Gram-negative strains. Among peptides, 5a and 6a demonstrated the highest antimicrobial activity. In combination with 11 commercially available antibiotics, 5a and 6a showed remarkable synergism against a large panel of resistant pathogens. Hemolysis (HC50 = 340 μg/mL) and cell viability against mammalian cells demonstrated the selective lethal action of 5a against bacteria over mammalian cells. Calcein dye leakage and scanning electron microscopy studies revealed the membranolytic effect of 5a. Moreover, the stability in human plasma (t1/2 = 3 h) and the negligible ability of pathogens to develop resistance further reflect the potential of 5a for further development as a peptide-based antibiotic.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Representative chemical structures of cyclic peptides [R4W4] (1), [R5W4] (5a), [R5W5] (5b), [R6W4] (6a), and [R6W5] (6b).
Scheme 1
Scheme 1. Solid-Phase Synthesis of [R5W4] (5b) as a Representative Example
Figure 2
Figure 2
Cytotoxicity assay of the lead cyclic peptide 5a. The results represent the data obtained from the experiments performed in triplicate (incubation for 24 h). DMSO (30%) was used as a positive control. The cells treated with DMSO (30%) showed 7–11% cell viability compared to nontreated (NT) cells having 100% cell viability.
Figure 3
Figure 3
Bactericidal kinetics of the lead cyclic peptide (5a) and standard antibiotics (daptomycin, polymyxin B, and ciprofloxacin) against MRSA (A1–A3) and E. coli (B1–B3) at the MIC and 4× the MIC. The data obtained are from the experiments performed in triplicate.
Figure 4
Figure 4
Concentration-dependent leakage of the calcein dye from bacterial membrane-mimicking (A1,A2) and mammalian membrane-mimicking (B1,B2) liposomes. 5a (A1,B1) and daptomycin (A2,B2). The data obtained are from the experiments performed in triplicate.
Figure 5
Figure 5
FE-SEM images of MRSA (A1,B1) and E. coli (A2,B2). Mid-logarithmic-phase bacterial cells were incubated with 5a (A2,B2) at a final concentration of 4× the MIC for 1 h. The control (A1,A2) was done without peptides.
Figure 6
Figure 6
Resistance induction after 18 repeated times of exposure of the lead cyclic peptide (5a) and standard antibiotics (daptomycin, polymyxin B, and ciprofloxacin) against (A1) S. aureus (ATCC 29213), (A2) MRSA (ATCC BAA-1556), (B1) E. coli (ATCC 25922), and (B2) E. coli (ATCC BAA-2452). The data represent the experiments performed in triplicate.
Figure 7
Figure 7
In vitro enzymatic stability assay of the lead cyclic peptides 5a in human plasma. The data represent the percentage of undegraded peptides measured using Q-TOF LC/MS as the area under the curve in the extracted ion chromatogram. The data obtained are from three independent experiments.
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