Peptoid-based antimicrobial strategies against polymyxin-resistant Gram-negative bacteria

AIMS: Polymyxins remain the mainstay antibiotic for the treatment of infections caused by multidrug-resistant bacteria. However, with the increase in the use of polymyxins, the simultaneous rise of polymyxin-resistance cases has been another global threat, necessitating the need for novel therapeutic strategies. This work aimed to evaluate the antibacterial activity of cationic peptoids against polymyxin-resistant bacteria of global priority. METHODS AND RESULTS: Three paired polymyxin-sensitive/polymyxin-resistant strains were included, along with two clinical isolates and one reference strain. Out of nine cationic peptoids, TM8 showed the most potent activity against the polymyxin-resistant bacteria with a geometric mean minimum inhibitory concentration (MIC) of 15.6 μg mL-1. The MIC of TM8 was 2-fold higher in polymyxin-resistant cases. TM8 synergized with colistin, rifampicin, and ciprofloxacin in polymyxin-resistant bacteria with reductions in MIC of antibiotics ranging from 8- to 64-fold. Enterobacter cloacae did not develop resistance to TM8 upon repeated subpassage at its sub-MIC, whereas it evolved to resist ciprofloxacin by sixty-four-fold under the same conditions. A concentration-dependent membrane-disruptive potential activity was noted in flow cytometry using live-dead staining. The impact of monovalent cations was small (≤2-fold change), while in the presence of divalent cations, the MIC of TM8 increased up to 4-fold. CONCLUSION: This study presents TM8 as a potential candidate antimicrobial against polymyxin-resistant bacteria. Further studies are recommended focusing on safety, pharmacokinetics, and pharmacodynamics of this compound.