Mechanism of Action and Resistance Evasion of an Antimicrobial Oligomer against Multidrug-Resistant Gram-Negative Bacteria

The last resort for treating multidrug-resistant (MDR) Pseudomonas aeruginosa and other MDR Gram-negative bacteria is a class of antibiotics called the polymyxins; however, polymyxin-resistant isolates have emerged. In response, antimicrobial peptides (AMPs) and their synthetic mimetics have been investigated as alternative therapeutic options. Oligothioetheramides (oligoTEAs) are a class of synthetic, sequence-defined oligomers composed of N-allylacrylamide monomers and an abiotic dithiol backbone that is resistant to serum degradation. Characteristic of other AMP mimetics, the precise balance between charge and hydrophobicity has afforded cationic oligoTEAs potent antimicrobial activity, particularly for the compound BDT-4G, which consists of a 1,4-butanedithiol backbone and guanidine pendant groups, the latter of which provides a cationic charge at physiological pH. However, the activity and mechanism of cationic oligoTEAs against MDR Gram-negative isolates have yet to be fully investigated. Herein, we demonstrated the potent antimicrobial activity of BDT-4G against clinical isolates of P. aeruginosa with a range of susceptibility profiles, assessed the kinetics of bactericidal activity, and further elucidated its mechanism of action. Activity was also evaluated against a panel of polymyxin-resistant isolates, including intrinsically-resistant species. We demonstrate that BDT-4G can evade some of the mechanisms conferring resistance to polymyxin B and thus may have therapeutic potential.