Metabolomic and molecular insights into adenosine triphosphate synthase inhibitors from Micromonospora sp. as novel antimicrobial agents against multidrug-resistant Gram-negative pathogens of enteric origin

• Published in: Letters in applied microbiology Vol. 78; no. 5
• Main Authors: El-Shatoury, Sahar A, Megawer, Hanan K, Hanora, Amro M, Makharita, Rabab R, Riesco, Raúl, Trujillo, Martha E, Nafie, Mohamed S
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.05.2025
• Subjects: Acetic acid; Adenosine triphosphate; Aerogenes; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - metabolism; Anti-Bacterial Agents - pharmacology; Antibiotic resistance; Antibiotics; Antimicrobial agents; ATP; ATP synthase; Bacteria; Bioactive compounds; Biological activity; Clinical isolates; Deoxyguanosine; Diethyl phthalate; DNA topoisomerase; Drug Resistance, Multiple, Bacterial - drug effects; E coli; Enterobacter aerogenes - drug effects; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Escherichia coli - drug effects; Ethyl acetate; Gene sequencing; Gram-Negative Bacteria - drug effects; Humans; Melibiose; Metabolites; Metabolomics; Microbial Sensitivity Tests; Micromonospora; Micromonospora - chemistry; Micromonospora - classification; Micromonospora - genetics; Micromonospora - metabolism; Molecular docking; Molecular modelling; Multidrug resistance; NMR; NMR spectroscopy; Nuclear magnetic resonance; Oligomycin; Oligomycin A; Pharmacology; RNA, Ribosomal, 16S - genetics; rRNA 16S; Spectroscopy; actinobacteria; Micromonospora spp; enteric-originated pathogens; molecular docking; antibiotic resistance
• ISSN: 1472-765X; 0266-8254; 1472-765X
• DOI: 10.1093/lambio/ovaf064

The overuse of antibiotics has accelerated the emergence of antibiotic-resistant bacteria, necessitating alternative treatment options. Micromonospora spp., known for producing bioactive metabolites, is a promising source of novel antimicrobials. This study evaluated the antimicrobial potential of metabolic ethyl-acetate extracts from three Micromonospora strains against multidrug-resistant (MDR) Gram-negative clinical isolates of enteric origin. Using the Kirby–Bauer modified disc diffusion method, following Clinical and Laboratory Standards Institute guidelines, the extract from Micromonospora strain 65SH exhibited the most potent activity, with minimum inhibitory concentrations of 25 µg/ml against Enterobacter aerogenes and 12.5 µg/ml against Escherichia coli. 16S rRNA gene sequencing identified the strain as closely related to Micromonospora fluminis (99.6% similarity). Further analysis using LC-QTOF-MS/MS non-targeted metabolomics identified six bioactive compounds—melibiose, oligomycin A, queuine, heptelidic acid, diethyl phthalate, and 2′-deoxyguanosine—linked to the inhibition of bacterial enzymes essential for proliferation. Molecular modeling suggested that these compounds disrupt E. coli ATP synthase and inhibit ATP-dependent bacterial topoisomerases. This study integrates metabolomics, molecular docking, and genomics, offering robust mechanistic insights into ATP synthase inhibition. Future research will include fecal isolate testing, detailed structural elucidation using nuclear magnetic resonance (NMR) spectroscopy, and experimental validation to explore the therapeutic potential of Micromonospora-derived compounds.