7p7t › Citations

Structural basis for PoxtA-mediated resistance to phenicol and oxazolidinone antibiotics.

<div class='caption-title'>Alignment of the ARDs from diverse bacterial ABCFs.</div>
<div class='caption-title'>Context-dependent ribosomal stalling induced by linezolid is countered by PoxtA.</div>
<div class='caption-title'>Cryo-EM structures of PoxtA–70S complexes.</div>
Crowe-McAuliffe C, Murina V, Turnbull KJ, Huch S, Kasari M, Takada H, Nersisyan L, Sundsfjord A, Hegstad K, Atkinson GC, Pelechano V, Wilson DN, Hauryliuk V
OpenAccess logo Nat Commun 13 1860 (2022)
Related entries: 7p7q, 7p7r, 7p7s, 7p7u

Cited: 15 times
EuropePMC logo PMID: 35387982

Abstract

PoxtA and OptrA are ATP binding cassette (ABC) proteins of the F subtype (ABCF). They confer resistance to oxazolidinone and phenicol antibiotics, such as linezolid and chloramphenicol, which stall translating ribosomes when certain amino acids are present at a defined position in the nascent polypeptide chain. These proteins are often encoded on mobile genetic elements, facilitating their rapid spread amongst Gram-positive bacteria, and are thought to confer resistance by binding to the ribosome and dislodging the bound antibiotic. However, the mechanistic basis of this resistance remains unclear. Here we refine the PoxtA spectrum of action, demonstrate alleviation of linezolid-induced context-dependent translational stalling, and present cryo-electron microscopy structures of PoxtA in complex with the Enterococcus faecalis 70S ribosome. PoxtA perturbs the CCA-end of the P-site tRNA, causing it to shift by ∼4 Å out of the ribosome, corresponding to a register shift of approximately one amino acid for an attached nascent polypeptide chain. We postulate that the perturbation of the P-site tRNA by PoxtA thereby alters the conformation of the attached nascent chain to disrupt the drug binding site.

Reviews citing this publication (4)

  1. Vancomycin Resistance in Enterococcus and Staphylococcus aureus. Li G, Walker MJ, De Oliveira DMP. Microorganisms 11 24 (2022)
  2. Ribosome-targeting antibiotics and resistance via ribosomal RNA methylation. Jeremia L, Deprez BE, Dey D, Conn GL, Wuest WM. RSC Med Chem 14 624-643 (2023)
  3. Potential influence of antimicrobial resistance gene content in probiotic bacteria on the gut resistome ecosystems. Radovanovic M, Kekic D, Gajic I, Kabic J, Jovicevic M, Kekic N, Opavski N, Ranin L. Front Nutr 10 1054555 (2023)
  4. Innovative Phospholipid Carriers: A Viable Strategy to Counteract Antimicrobial Resistance. Nicolosi D, Petronio Petronio G, Russo S, Di Naro M, Cutuli MA, Russo C, Di Marco R. Int J Mol Sci 24 15934 (2023)

Articles citing this publication (11)

  1. Structural basis for the inability of chloramphenicol to inhibit peptide bond formation in the presence of A-site glycine. Syroegin EA, Aleksandrova EV, Polikanov YS. Nucleic Acids Res 50 7669-7679 (2022)
  2. Genome-encoded ABCF factors implicated in intrinsic antibiotic resistance in Gram-positive bacteria: VmlR2, Ard1 and CplR. Obana N, Takada H, Crowe-McAuliffe C, Iwamoto M, Egorov AA, Wu KJY, Chiba S, Murina V, Paternoga H, Tresco BIC, Nomura N, Myers AG, Atkinson GC, Wilson DN, Hauryliuk V. Nucleic Acids Res 51 4536-4554 (2023)
  3. Structural basis for HflXr-mediated antibiotic resistance in Listeria monocytogenes. Koller TO, Turnbull KJ, Vaitkevicius K, Crowe-McAuliffe C, Roghanian M, Bulvas O, Nakamoto JA, Kurata T, Julius C, Atkinson GC, Johansson J, Hauryliuk V, Wilson DN. Nucleic Acids Res 50 11285-11300 (2022)
  4. Structural conservation of antibiotic interaction with ribosomes. Paternoga H, Crowe-McAuliffe C, Bock LV, Koller TO, Morici M, Beckert B, Myasnikov AG, Grubmüller H, Nováček J, Wilson DN. Nat Struct Mol Biol 30 1380-1392 (2023)
  5. Linezolid-Resistant Enterococcus faecalis of Chicken Origin Harbored Chromosome-Borne optrA and Plasmid-Borne cfr, cfr(D), and poxtA2 Genes. Tang B, Zou C, Schwarz S, Xu C, Hao W, Yan XM, Huang Y, Ni J, Yang H, Du XD, Shan X. Microbiol Spectr 11 e0274122 (2023)
  6. Persistence of transferable oxazolidinone resistance genes in enterococcal isolates from a swine farm in China. Huang Z, Bai Y, Wang Q, Yang X, Zhang T, Chen X, Wang H. Front Microbiol 13 1010513 (2022)
  7. Prevalence and Genetic Analysis of Resistance Mechanisms of Linezolid-Nonsusceptible Enterococci in a Tertiary Care Hospital Examined via Whole-Genome Sequencing. Hu Y, Won D, Nguyen LP, Osei KM, Seo Y, Kim J, Lee Y, Lee H, Yong D, Choi JR, Lee K. Antibiotics (Basel) 11 1624 (2022)
  8. Regulation of the macrolide resistance ABC-F translation factor MsrD. Fostier CR, Ousalem F, Leroy EC, Ngo S, Soufari H, Innis CA, Hashem Y, Boël G. Nat Commun 14 3891 (2023)
  9. Detection of an Enterococcus faecium Carrying a Double Copy of the PoxtA Gene from Freshwater River, Italy. Cinthi M, Coccitto SN, Morroni G, D'Achille G, Brenciani A, Giovanetti E. Antibiotics (Basel) 11 1618 (2022)
  10. Gene rppA co-regulated by LRR, SigA, and CcpA mediates antibiotic resistance in Bacillus thuringiensis. Cai X, Li X, Qin J, Zhang Y, Yan B, Cai J. Appl Microbiol Biotechnol 106 5687-5699 (2022)
  11. The ABCF proteins in Escherichia coli individually cope with 'hard-to-translate' nascent peptide sequences. Chadani Y, Yamanouchi S, Uemura E, Yamasaki K, Niwa T, Ikeda T, Kurihara M, Iwasaki W, Taguchi H. Nucleic Acids Res 52 5825-5840 (2024)


Related citations provided by authors (2)

  1. Structural basis for PoxtA-mediated resistance to Phenicol and Oxazolidinone antibiotics. Crowe-McAuliffe C, Murina V, Kasari M, Takada H, Turnbull KJ, Sundsfjord A, Hegstad K, Atkinson GC, Wilson DN, Hauryliuk V Biorxiv - (2021)
  2. The Enterococcus Cassette Chromosome, a Genomic Variation Enabler in Enterococci.. Sivertsen A, Janice J, Pedersen T, Wagner TM, Hegstad J, Hegstad K mSphere 3 (2018)

Quick links