Proteomic analysis of metronidazole resistance in the human facultative pathogen Bacteroides fragilis .

Autor:	Paunkov A; Institute for Specific Prophylaxis and Tropical Medicine, Center for Pathophysiology, Infectiology, and Immunology, Medical University of Vienna, Vienna, Austria., Hummel K; VetCore Facility for Research, University of Veterinary Medicine, Vienna, Austria., Strasser D; Institute for Specific Prophylaxis and Tropical Medicine, Center for Pathophysiology, Infectiology, and Immunology, Medical University of Vienna, Vienna, Austria., Sóki J; Faculty of Medicine, Institute of Medical Microbiology, University of Szeged, Szeged, Hungary., Leitsch D; Institute for Specific Prophylaxis and Tropical Medicine, Center for Pathophysiology, Infectiology, and Immunology, Medical University of Vienna, Vienna, Austria.
Jazyk:	angličtina
Zdroj:	Frontiers in microbiology [Front Microbiol] 2023 Mar 31; Vol. 14, pp. 1158086. Date of Electronic Publication: 2023 Mar 31 (Print Publication: 2023).
DOI:	10.3389/fmicb.2023.1158086
Abstrakt:	The anaerobic gut bacteria and opportunistic pathogen Bacteroides fragilis can cause life-threatening infections when leaving its niche and reaching body sites outside of the gut. The antimicrobial metronidazole is a mainstay in the treatment of anaerobic infections and also highly effective against Bacteroides spp. Although resistance rates have remained low in general, metronidazole resistance does occur in B . fragilis and can favor fatal disease outcomes. Most metronidazole-resistant Bacteroides isolates harbor nim genes, commonly believed to encode for nitroreductases which deactivate metronidazole. Recent research, however, suggests that the mode of resistance mediated by Nim proteins might be more complex than anticipated because they affect the cellular metabolism, e.g., by increasing the activity of pyruvate:ferredoxin oxidoreductase (PFOR). Moreover, although nim genes confer only low-level metronidazole resistance to Bacteroides , high-level resistance can be much easier induced in the laboratory in the presence of a nim gene than without. Due to these observations, we hypothesized that nim genes might induce changes in the B . fragilis proteome and performed comparative mass-spectrometric analyses with B . fragilis 638R, either with or without the nimA gene. Further, we compared protein expression profiles in both strains after induction of high-level metronidazole resistance. Interestingly, only few proteins were repeatedly found to be differentially expressed in strain 638R with the nimA gene, one of them being the flavodiiron protein FprA, an enzyme involved in oxygen scavenging. After induction of metronidazole resistance, a far higher number of proteins were found to be differentially expressed in 638R without nimA than in 638R with nimA . In the former, factors for the import of hemin were strongly downregulated, indicating impaired iron import, whereas in the latter, the observed changes were not only less numerous but also less specific. Both resistant strains, however, displayed a reduced capability of scavenging oxygen. Susceptibility to metronidazole could be widely restored in resistant 638R without nimA by supplementing growth media with ferrous iron sulfate, but not so in resistant 638R with the nimA gene. Finally, based on the results of this study, we present a novel hypothetic model of metronidazole resistance and NimA function. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2023 Paunkov, Hummel, Strasser, Sóki and Leitsch.)
Databáze:	MEDLINE
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