Dataset Information

Serendipitous Discovery of a Highly Active and Selective Resistance-Modifying Agent for Colistin-Resistant Gram-Negative Bacteria.

ABSTRACT: Antibiotic resistance is a growing global health concern. Colistin is one of the last-resort antibiotics that treats multidrug-resistant (MDR) Gram-negative bacterial infection. However, bacteria resistant to colistin have become increasingly prevalent. Using a bacterial whole-cell screen of a fragment-based library, one compound was discovered to resensitize MDR Escherichia coli AR-0493 to colistin with low mammalian toxicity. Interestingly, postscreening validation studies identified a highly related yet distinct compound as the actual substance responsible for the activity. Further studies showed that this novel resistance-modifying agent is not only very potent but also highly selective to potentiate the activity of polymyxin family antibiotics in a wide range of MDR Gram-negative bacteria. Thus, it may be further developed as a combination therapy to prolong the life span of colistin in the clinic.

SUBMITTER: Gao Y

PROVIDER: S-EPMC9016814 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Serendipitous Discovery of a Highly Active and Selective Resistance-Modifying Agent for Colistin-Resistant Gram-Negative Bacteria.

Gao Yuefeng Y Dutta Somnath S Wang Xiang X

ACS omega 20220330 14

Antibiotic resistance is a growing global health concern. Colistin is one of the last-resort antibiotics that treats multidrug-resistant (MDR) Gram-negative bacterial infection. However, bacteria resistant to colistin have become increasingly prevalent. Using a bacterial whole-cell screen of a fragment-based library, one compound was discovered to resensitize MDR <i>Escherichia coli</i> AR-0493 to colistin with low mammalian toxicity. Interestingly, postscreening validation studies identified a ...[more]

PMID: 35449921

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Project description:Polymyxin is used as a last resort antibiotics for infections caused by multi-drug resistant (MDR) Gram-negative bacteria and is often combined with other antibiotics to improve clinical effectiveness. However, the synergism of colistin and other antibiotics remains obscure. Here, we revealed a notable synergy between colistin and flavomycin, which was traditionally used as an animal growth promoter and has limited activity against Gram-negative bacteria, using checkerboard assay and time-kill curve analyses. The importance of membrane penetration induced by colistin was assessed by examining the intracellular accumulation of flavomycin and its antimicrobial impact on Escherichia coli (E. coli) strains with truncated lipopolysaccharides. Besides, a mutation in the flavomycin binding site was created to confirm its role in the observed synergy. This synergy is manifested as an augmented penetration of the E. coli outer membrane by colistin, leading to increased intracellular accumulation of flavomycin and enhanced cell killing thereafter. The observed synergy was dependent on the antimicrobial activity of flavomycin, as mutation of its binding site abolished the synergy. In vivo studies confirmed the efficacy of colistin combined with flavomycin against MDR E. coli infections. This study is the first to demonstrate the synergistic effect between colistin and flavomycin, shedding light on their respective roles in this synergism. Therefore, we propose flavomycin as an adjuvant to enhance the potency of colistin against MDR Gram-negative bacteria.ImportanceColistin is a critical antibiotic in combating multi-drug resistant Gram-negative bacteria, but the emergence of mobilized colistin resistance (mcr) undermines its effectiveness. Previous studies have found that colistin can synergy with various drugs; however, its exact mechanisms with hydrophobic drugs are still unrevealed. Generally, the membrane destruction of colistin is thought to be the essential trigger for its interactions with its partner drugs. Here, we use clustered regularly interspaced palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) for specifically mutating the binding site of one hydrophobic drug (flavomycin) and show that antimicrobial activity of flavomycin is critical for the synergy. Our results first give the evidence that the synergy is set off by colistin's membrane destruction and operated the final antimicrobial function by its partner drugs.

Dataset Information

Serendipitous Discovery of a Highly Active and Selective Resistance-Modifying Agent for Colistin-Resistant Gram-Negative Bacteria.

Publications

Serendipitous Discovery of a Highly Active and Selective Resistance-Modifying Agent for Colistin-Resistant Gram-Negative Bacteria.

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