Exploitation of a novel adjuvant for polymyxin B against multidrug-resistant Acinetobacter baumannii
Seon-Yeong Kim1,2, Hwi Won Seo1, Min-Seon Park1
1Infection Disease Research Center, KRIBB, Daejeon 34141, South Korea.
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.
Insights
A new compound, PA108, enhances polymyxin B
Area of Science:
- Microbiology and Infectious Diseases
- Pharmacology and Drug Discovery
Background:
- Polymyxin antibiotics are last-resort treatments for resistant bacteria but have toxicity concerns.
- Rising antibiotic resistance necessitates novel therapeutic strategies beyond direct antimicrobial action.
- Polymyxin-resistant microorganisms pose a significant clinical challenge.
Purpose of the Study:
- To develop novel therapies that enhance existing antibiotics, thereby circumventing antibiotic resistance.
- To identify compounds that act as adjuvants to polymyxin B, restoring its efficacy against resistant strains.
- To explore non-antimicrobial approaches to combat bacterial infections.
Main Methods:
- High-throughput screening using bacterial respiration to identify compounds potentiating polymyxin B activity.
- In vitro and in vivo validation of identified adjuvants.
- Mechanistic studies including membrane depolarization and transcriptome analysis.
Main Results:
- PA108, a novel compound, demonstrated adjuvant activity, enabling polymyxin B to eradicate polymyxin-resistant *A. baumannii* and other species at sub-inhibitory concentrations.
- PA108 lacks self-bactericidal activity, confirming its role as an antibiotic adjuvant.
- Co-treatment with PA108 and polymyxin B showed no toxicity in cell lines or mice, significantly improving survival and reducing bacterial load in vivo.
Conclusions:
- Antibiotic adjuvants like PA108 offer a promising strategy to overcome bacterial antibiotic resistance.
- Enhancing the efficiency of existing antibiotics through adjuvants is a viable approach to combatting the growing threat of resistant infections.
- This study highlights a new avenue for drug development that does not directly promote further antibiotic resistance.
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