Exploitation of a novel adjuvant for polymyxin B against multidrug-resistant Acinetobacter baumannii

Abstract

Background: Although polymyxin has been used as a last-resort antibiotic against resistant bacteria, its use is restricted due to nephrotoxicity and neurotoxicity. While the present antibiotic resistance issue compels clinicians to reconsider polymyxin use in severe illness cases, polymyxin-resistant microorganisms exert an effect. Objectives: To address the issue of antibiotic resistance, the cycle of developing new antibiotics to counteract emerging resistance must be discontinued. Here we tried to develop novel therapies that do not rely on direct antimicrobial activity and thus do not promote antibiotic resistance. Methods: By a high-throughout screening system based on bacterial respiration, chemical compounds accelerating the antimicrobial effects of polymyxin B were screened. In vitro and in vivo tests were performed to validate adjuvanticity. In addition, membrane depolarization and total transcriptome analysis were used to determine molecular mechanisms. Results: PA108, a newly discovered chemical compound, was used to eradicate polymyxin-resistant A. baumannii and three other species in the presence of polymyxin B at concentrations less than the MIC. Since this molecule lacks self-bactericidal action, we hypothesized that PA108 acts as an antibiotic adjuvant, enhancing the antimicrobial activity of polymyxin B against resistant bacteria. At working concentrations, no toxicity was observed in cell lines or mice, although co-treatment with PA108 and polymyxin B increased survival of infected mouse and decreased bacterial loads in organs. Conclusions: Boosting antibiotic efficiency through the use of antibiotic adjuvants holds significant promise for tackling the rise in bacterial antibiotic resistance.