Amphiphilic nebramine analogs synergize with β-lactam/β-lactamase inhibitor combinations, including cefepime–taniborbactam and meropenem–xeruborbactam against metallo-β-lactamase-carrying Pseudomonas aeruginosa

Abstract

Cefepime–taniborbactam (FEP–TAN) and meropenem–xeruborbactam (MEM–XER) are β-lactam–β-lactamase inhibitor (BL–BLI) combinations currently in development and both projected to treat metallo-β-lactamase (MBL)-producing Gram-negative pathogens. Among Gram-negative pathogens, the low permeability of the outer membrane of Pseudomonas aeruginosa poses unique challenges to drug discovery in general and to BL–BLIs in particular. This study set out to augment β-lactam antibiotic potency by enhancing outer membrane permeability of P. aeruginosa using novel amphiphilic aminoglycoside-based outer membrane permeabilizers. Amphiphilic nebramines acting as outer membrane permeabilizers, were synthesized and evaluated in combination with β-lactam antibiotics and BL–BLIs against P. aeruginosa clinical isolates harbouring a number of resistance determinants, including MBLs. Dually guanidinylated and C-5-alkylated analogs of nebramine were able to sensitize MBL-carrying P. aeruginosa to various BL–BLIs. The amphiphilic nebramine derivative, compound 4, synergized with multiple β-lactam antibiotics and BL–BLIs including aztreonam–avibactam (ATM–AVI), FEP–TAN and MEM–XER against multidrug-resistant P. aeruginosa isolates. In particular, compound 4 + ATM–AVI, restored susceptibility to all nine β-lactamase (including MBL)-harbouring P. aeruginosa strains that were previously resistant to aztreonam. Compound 4 was found to be less toxic than both polymyxin B and its corresponding amphiphilic tobramycin counterpart (compound 7) in human renal cell lines, RPTEC and HK-2. Overall, our study suggests that addition of compound 4 alongside next-generation BL–BLIs such as FEP–TAN, MEM–XER as well as the recently approved ATM–AVI combination can overcome intrinsic and acquired in vitro P. aeruginosa resistance determinants that confer high-level resistance to β-lactam antibiotics.