{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Rudra P"],"funding":["Cystic Fibrosis Foundation","NIAID NIH HHS","Office of Extramural Research, National Institutes of Health"],"pagination":["629-634"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC6955381"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["117(1)"],"pubmed_abstract":["Antibiotic resistance in bacteria is typically conferred by proteins that function as efflux pumps or enzymes that modify either the drug or the antibiotic target. Here we report an unusual mechanism of resistance to macrolide-lincosamide antibiotics mediated by mycobacterial HflX, a conserved ribosome-associated GTPase. We show that deletion of the <i>hflX</i> gene in the pathogenic <i>Mycobacterium abscessus</i>, as well as the nonpathogenic <i>Mycobacterium smegmatis</i>, results in hypersensitivity to the macrolide-lincosamide class of antibiotics. Importantly, the level of resistance provided by <i>Mab_hflX</i> is equivalent to that conferred by <i>erm41</i>, implying that <i>hflX</i> constitutes a significant resistance determinant in <i>M. abscessus</i> We demonstrate that mycobacterial HflX associates with the 50S ribosomal subunits in vivo and can dissociate purified 70S ribosomes in vitro, independent of GTP hydrolysis. The absence of HflX in a <i>ΔMs_hflX</i> strain also results in a significant accumulation of 70S ribosomes upon erythromycin exposure. Finally, a deletion of either the N-terminal or the C-terminal domain of HflX abrogates ribosome splitting and concomitantly abolishes the ability of mutant proteins to mediate antibiotic tolerance. Together, our results suggest a mechanism of macrolide-lincosamide resistance in which the mycobacterial HflX dissociates antibiotic-stalled ribosomes and rescues the bound mRNA. Given the widespread presence of <i>hflX</i> genes, we anticipate this as a generalized mechanism of macrolide resistance used by several bacteria."],"journal":["Proceedings of the National Academy of Sciences of the United States of America"],"pubmed_title":["Mycobacterial HflX is a ribosome splitting factor that mediates antibiotic resistance."],"pmcid":["PMC6955381"],"funding_grant_id":["GHOSH18G0","R21 AI146774","1 R21 AI146774"],"pubmed_authors":["Ghosh P","Hurst-Hess KR","Partida-Miranda A","Rudra P","Cotten KL"],"additional_accession":[]},"is_claimable":false,"name":"Mycobacterial HflX is a ribosome splitting factor that mediates antibiotic resistance.","description":"Antibiotic resistance in bacteria is typically conferred by proteins that function as efflux pumps or enzymes that modify either the drug or the antibiotic target. Here we report an unusual mechanism of resistance to macrolide-lincosamide antibiotics mediated by mycobacterial HflX, a conserved ribosome-associated GTPase. We show that deletion of the <i>hflX</i> gene in the pathogenic <i>Mycobacterium abscessus</i>, as well as the nonpathogenic <i>Mycobacterium smegmatis</i>, results in hypersensitivity to the macrolide-lincosamide class of antibiotics. Importantly, the level of resistance provided by <i>Mab_hflX</i> is equivalent to that conferred by <i>erm41</i>, implying that <i>hflX</i> constitutes a significant resistance determinant in <i>M. abscessus</i> We demonstrate that mycobacterial HflX associates with the 50S ribosomal subunits in vivo and can dissociate purified 70S ribosomes in vitro, independent of GTP hydrolysis. The absence of HflX in a <i>ΔMs_hflX</i> strain also results in a significant accumulation of 70S ribosomes upon erythromycin exposure. Finally, a deletion of either the N-terminal or the C-terminal domain of HflX abrogates ribosome splitting and concomitantly abolishes the ability of mutant proteins to mediate antibiotic tolerance. Together, our results suggest a mechanism of macrolide-lincosamide resistance in which the mycobacterial HflX dissociates antibiotic-stalled ribosomes and rescues the bound mRNA. Given the widespread presence of <i>hflX</i> genes, we anticipate this as a generalized mechanism of macrolide resistance used by several bacteria.","dates":{"release":"2020-01-01T00:00:00Z","publication":"2020 Jan","modification":"2024-11-20T17:30:04.403Z","creation":"2020-06-26T07:04:56Z"},"accession":"S-EPMC6955381","cross_references":{"pubmed":["31871194"],"doi":["10.1073/pnas.1906748117"]}}