Affiliation:
1. Department of Chemistry, Shanghai Stomatological Hospital, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200000, China
2. Changhai Hospital, The Naval Military Medical University, Shanghai 200433, China
Abstract
Bacterial antimicrobial resistance (AMR) is among the most significant challenges to current human society. Exposing bacteria to antibiotics can activate their self-saving responses, e.g., filamentation, leading to the development of bacterial AMR. Understanding the molecular changes during the self-saving responses can reveal new inhibition methods of drug-resistant bacteria. Herein, we used an online microfluidics mass spectrometry system for real-time characterization of metabolic changes of bacteria during filamentation under the stimulus of antibiotics. Significant pathways, e.g., nucleotide metabolism and coenzyme A biosynthesis, correlated to the filamentation of extended-spectrum beta-lactamase-producing
Escherichia coli
(ESBL-
E. coli
) were identified. A cyclic dinucleotide, c-di-GMP, which is derived from nucleotide metabolism and reported closely related to bacterial resistance and tolerance, was observed significantly up-regulated during the bacterial filamentation. By using a chemical inhibitor, ebselen, to inhibit diguanylate cyclases which catalyzes the synthesis of c-di-GMP, the minimum inhibitory concentration of ceftriaxone against ESBL-
E. coli
was significantly decreased. This inhibitory effect was also verified with other ESBL-
E. coli
strains and other beta-lactam antibiotics, i.e., ampicillin. A mutant strain of ESBL-
E. coli
by knocking out the
dgcM
gene was used to demonstrate that the inhibition of the antibiotic resistance to beta-lactams by ebselen was mediated through the inhibition of the diguanylate cyclase DgcM and the modulation of c-di-GMP levels. Our study uncovers the molecular changes during bacterial filamentation and proposes a method to inhibit antibiotic-resistant bacteria by combining traditional antibiotics and chemical inhibitors against the enzymes involved in bacterial self-saving responses.
Funder
MOST | National Natural Science Foundation of China
Publisher
Proceedings of the National Academy of Sciences
Reference73 articles.
1. Antibiotic resistance in bacteria - an emerging public health problem;Komolafe O. O.;Malawi Med. J.,2003
2. World Health Organization Report: Current Crisis of Antibiotic Resistance
3. Extended-Spectrum β-Lactamases: a Clinical Update
4. CDC Antibiotic resistance threats in the United States (CDC Centers for Disease Control and Prevention Department of Health and Human Services 2019).
5. Optimized arylomycins are a new class of Gram-negative antibiotics
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