Expanding the Utility of Colistin Adjuvants To Encompass Next-Generation Polymyxins against Polymyxin-Resistant Acinetobacter baumannii and Klebsiella pneumoniae

Abstract

Abstract Current treatment options for multidrug-resistant (MDR) Gram-negative infections are effectively limited to last-resort antibiotics, such as the polymyxins. Clinical use of polymyxins remains limited due to significant nephrotoxic side effects, and is further limited as a result of increasing polymyxin resistance. The novel polymyxin antibiotic, SPR206, developed in 2019, retains potency against polymyxin-susceptible Gram-negative bacteria while showing no adverse side effects in Phase 1 clinical trials. However, resistance to SPR206 is anticipated through the same mechanisms that drive resistance to the currently available polymyxins. We have reported several small-molecule polymyxin adjuvant scaffolds that reverse resistance in polymyxin-resistant Gram-negative bacteria. Herein, we describe the evaluation of six previously reported colistin adjuvants for the modulation of SPR206 activity in polymyxin-resistant Acinetobacter baumannii and Klebsiella pneumoniae. Several adjuvants exhibit equipotent or increased activity with SPR206 compared to that with colistin, and maintain SPR206 adjuvant activity against a panel of clinical isolates. Additionally, bacteria do not evolve resistance to the combination of adjuvant NDM-27 and SPR206 over a seven-day period, with low spontaneous mutation frequencies of 4.54 × 10–8 (AB4106) and 3.32 × 10–9 (KPB9) at 4X the SPR206 minimum inhibitory concentration. Overall, these data support the potential use of previously developed adjuvants to augment the activity of next-generation polymyxins.