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A Macromolecule Reversing Antibiotic Resistance Phenotype and Repurposing Drugs as Potent Antibiotics.

ABSTRACT: In order to mitigate antibiotic resistance, a new strategy to increase antibiotic potency and reverse drug resistance is needed. Herein, the translocation mechanism of an antimicrobial guanidinium-functionalized polycarbonate is leveraged in combination with traditional antibiotics to afford a potent treatment for drug-resistant bacteria. Particularly, this polymer-antibiotic combination approach reverses rifampicin resistance phenotype in Acinetobacter baumannii demonstrating a 2.5 × 105-fold reduction in minimum inhibitory concentration (MIC) and a 4096-fold reduction in minimum bactericidal concentration (MBC). This approach also enables the repurposing of auranofin as an antibiotic against multidrug-resistant (MDR) Gram-negative bacteria with a 512-fold MIC and 128-fold MBC reduction, respectively. Finally, the in vivo efficacy of polymer-rifampicin combination is demonstrated in a MDR bacteremia mouse model. This combination approach lays foundational ground rules for a new class of antibiotic adjuvants capable of reversing drug resistance phenotype and repurposing drugs against MDR Gram-negative bacteria.

SUBMITTER: Ding X

PROVIDER: S-EPMC7503100 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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A Macromolecule Reversing Antibiotic Resistance Phenotype and Repurposing Drugs as Potent Antibiotics.

Ding Xin X Yang Chuan C Moreira Wilfried W Yuan Peiyan P Periaswamy Balamurugan B de Sessions Paola Florez PF Zhao Huimin H Tan Jeremy J Lee Ashlynn A Ong Kai Xun KX Park Nathaniel N Liang Zhen Chang ZC Hedrick James L JL Yang Yi Yan YY

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20200721 17

In order to mitigate antibiotic resistance, a new strategy to increase antibiotic potency and reverse drug resistance is needed. Herein, the translocation mechanism of an antimicrobial guanidinium-functionalized polycarbonate is leveraged in combination with traditional antibiotics to afford a potent treatment for drug-resistant bacteria. Particularly, this polymer-antibiotic combination approach reverses rifampicin resistance phenotype in <i>Acinetobacter baumannii</i> demonstrating a 2.5 × 10< ...[more]

PMID: 32995131

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Project description:The reversibility of antibiotic resistance is theoretically attractive due to the prospect of restoring the clinical potency of antibiotics. It is important to find out the factors that affect the reversibility of antibiotic resistance. Here, an mcr-1-positive multidrug-resistant (MDR) environmental Escherichia coli isolate was successively passaged under four antibiotic-free culture conditions. The relative abundances of multiple antibiotic resistance genes (ARGs) kept decreasing during the successive passages. The linear correlations between abundances of ARGs on the same MDR plasmid reflected that the decay of antibiotic resistance during the passage was mainly due to the elimination of the MDR plasmid (pMCR_W5-6). Colistin-susceptible strains were isolated at the end of the passage. The whole-genome sequencing of two susceptible isolates detected the elimination of the MDR plasmid and deletion of the mcr-1 gene. Deletions of DNA fragments from chromosome and plasmid were closely related to a variety of insertion sequences (ISs). The results of coculture of resistant and susceptible strains at different antibiotic concentrations indicated that the high fitness cost led to the poor stability of mobile ARGs. Strict control of the use of antibiotics can at least reverse the severe antibiotic resistance caused by mobile ARGs of high fitness cost. IMPORTANCE The dissemination of bacterial antibiotic resistance is a serious threat to human health. The development of new antibiotics faces both economic and technological challenges. The reversibility of antibiotic resistance has become an important issue causing wide concern due to the prospect of restoring the clinical potency of antibiotics. Our study suggests that the high mobility of ARGs of high fitness cost may just reflect their poor stability. Therefore, strict control of the use of antibiotics can at least reverse the severe antibiotic resistance caused by mobile ARGs of high fitness cost. This study brings hope for the possibility of curbing the dissemination of antibiotic resistance.

Project description:Antibiotic resistance in our pathogens is medicine's climate change: caused by human activity, and resulting in more extreme outcomes. Resistance emerges in microbial populations when antibiotics act on phenotypic variance within the population. This can arise from either genotypic diversity (resulting from a mutation or horizontal gene transfer), or from differences in gene expression due to environmental variation, referred to as adaptive resistance. Adaptive changes can increase fitness allowing bacteria to survive at higher concentrations of antibiotics. They can also decrease fitness, potentially leading to selection for antibiotic resistance at lower concentrations. There are opportunities for other environmental stressors to promote antibiotic resistance in ways that are hard to predict using conventional assays. Exploiting our previous observation that commonly used herbicides can increase or decrease the minimum inhibitory concentration (MIC) of different antibiotics, we provide the first comprehensive test of the hypothesis that the rate of antibiotic resistance evolution under specified conditions can increase, regardless of whether a herbicide increases or decreases the antibiotic MIC. Short term evolution experiments were used for various herbicide and antibiotic combinations. We found conditions where acquired resistance arises more frequently regardless of whether the exogenous non-antibiotic agent increased or decreased antibiotic effectiveness. This is attributed to the effect of the herbicide on either MIC or the minimum selective concentration (MSC) of a paired antibiotic. The MSC is the lowest concentration of antibiotic at which the fitness of individuals varies because of the antibiotic, and is lower than MIC. Our results suggest that additional environmental factors influencing competition between bacteria could enhance the ability of antibiotics to select antibiotic resistance. Our work demonstrates that bacteria may acquire antibiotic resistance in the environment at rates substantially faster than predicted from laboratory conditions.

Dataset Information

A Macromolecule Reversing Antibiotic Resistance Phenotype and Repurposing Drugs as Potent Antibiotics.

Publications

A Macromolecule Reversing Antibiotic Resistance Phenotype and Repurposing Drugs as Potent Antibiotics.

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