Rifampicin is an effective antibiotic against mycobacterial and other bacterial infections, but resistance readily emerges in laboratory and clinical settings. We screened Escherichia coli for rifampicin resistance and identified numerous mutations to the gene encoding the β-chain of RNA polymerase (rpoB), including an unusual 9-nucleotide deletion mutation. Structural modeling of the deletion mutant indicates locations of potential steric clashes with rifampicin. Sequence conservation in the region near the deletion mutation suggests a similar mutation may also confer resistance during the treatment of tuberculosis.

Artsimovitch I, Vassylyeva MN, Svetlov D, Svetlov V, Perederina A, Igarashi N, et al: Allosteric modulation of the RNA polymerase catalytic reaction is an essential component of transcription control by rifamycins. Cell 2005;122:351-363.
Baquero MR, Nilsson AI, Turrientes MDC, Sandvang D, Galán JC, Martínez JL, et al: Polymorphic mutation frequencies in Escherichia coli: emergence of weak mutators in clinical isolates. J Bacteriol 2004;186:5538-5542.
Barrick JE, Kauth MR, Strelioff CC, Lenski RE: Escherichia coli rpoB mutants have increased evolvability in proportion to their fitness defects. Mol Biol Evol 2010;27:1338-1347.
Bjedov I, Tenaillon O, Souza V, Denamur E, Radman M, Gerard B, et al: Stress-induced mutagenesis in bacteria. Science 2003;300:1404-1409.
Campbell EA, Korzheva N, Mustaev A, Murakami K, Nair S, Goldfarb A, et al: Structural mechanism for rifampicin inhibition of bacterial RNA polymerase. Cell 2001;104:901-912.
DeLano WL: The PyMOL Molecular Graphics System, Version 1.8. Schrödinger LLC. 2014. http://www.pymol.org.
Galán JC, Turrientes MC, Baquero MR, Rodríguez-Alcayna M, Martínez-Amado J, Martínez JL, et al: Mutation rate is reduced by increased dosage of mutL gene in Escherichia coli K-12. FEMS Microbiol Lett 2007;275:263-269.
Gill SK, Garcia GA: Rifamycin inhibition of WT and Rif-resistant Mycobacterium tuberculosis and Escherichia coli RNA polymerases in vitro. Tuberculosis 2011;91:361-369.
Gillet-Markowska A, Louvel G, Fischer G: bz-rates: a web tool to estimate mutation rates from fluctuation analysis. G3 (Bethesda) 2015;5:2323-2327.
Hellmark B, Söderquist B, Unemo M: Simultaneous species identification and detection of rifampicin resistance in staphylococci by sequencing of the rpoB gene. Eur J Clin Microbiol Infect Dis 2009;28:183-190.
Jin DJ, Gross CA: Characterization of the pleiotropic phenotypes of rifampin-resistant rpoB mutants of Escherichia coli. J Bacteriol 1989;171:5229-5231.
Kang JY, Olinares PDB, Chen J, Campbell EA, Mustaev A, Chait BT, et al: Structural basis of transcription arrest by coliphage HK022 Nun in an Escherichia coli RNA polymerase elongation complex. Elife 2017;6:e25478.
Lin W, Mandal S, Degen D, Liu Y, Ebright YW, Li S, et al: Structural basis of Mycobacterium tuberculosis transcription and transcription inhibition. Mol Cell 2017;66:169-179.e8.
Luria S, Delbrück M: Mutations of bacteria from virus sensitivity to virus resistance. Genetics 1943;28:491-511.
Makiela-Dzbenska K, Jonczyk P, Schaaper RM, Fijalkowska IJ: Proofreading deficiency of Pol I increases the levels of spontaneous rpoB mutations in E. coli. Mutat Res Fundam Mol Mech Mutagen 2011;712:28-32.
McClure WR, Cech CL: On the mechanism of rifampicin inhibition of RNA synthesis. J Biol Chem 1978;253:8949-8956.
Molodtsov V, Nawarathne IN, Scharf NT, Kirchhoff PD, Showalter HDH, Garcia GA, et al: X-ray crystal structures of the Escherichia coli RNA polymerase in complex with benzoxazinorifamycins. J Med Chem 2013;56:4758-4763.
Molodtsov V, Scharf NT, Stefan MA, Garcia GA, Murakami KS: Structural basis for rifamycin resistance of bacterial RNA polymerase by the three most clinically important RpoB mutations found in Mycobacterium tuberculosis. Mol Microbiol 2017;103:1034-1045.
Murugan K, Kavitha K, Al-Sohaibani S: Rifampicin resistance among multi-resistant MRSA clinical isolates from Chennai, India, and their molecular characterization. Genet Mol Res 2015;14:2716-2725.
Sandgren A, Strong M, Muthukrishnan P, Weiner BK, Church GM, Murray MB: Tuberculosis drug resistance mutation database. PLoS Med 2009;6:0132-0136.
Sensi P: History of the development of rifampin. Rev Infect Dis 1983;5:S402-S406.
Telenti A, Imboden P, Marchesi F, Matter L, Schopfer K, Bodmer T, et al: Detection of rifampicin-resistance mutations in Mycobacterium tuberculosis. Lancet 1993;341:647-651.
Williams DL, Spring L, Collins L, Miller LP, Heifets LB, Gangadharam PRJ, et al: Contribution of rpoB mutations to development of rifamycin cross-resistance in Mycobacterium tuberculosis. Antimicrob Agents Chemother 1998;42:1853-1857.
Xu M, Zhou YN, Goldstein BP, Jin DJ: Cross-resistance of Escherichia coli RNA polymerases conferring rifampin resistance to different antibiotics. J Bacteriol 2005;187:2783-2792.
Yang J, Yan R, Roy A, Xu D, Poisson J, Zhang Y: The I-TASSER suite: protein structure and function prediction. Nat Meth 2015;12:7-8.
Ycart B, Veziris N: Unbiased estimation of mutation rates under fluctuating final counts. PLoS One 2014;9.e101434.
Zhou W, Shan W, Ma X, Chang W, Zhou X, Lu H, et al: Molecular characterization of rifampicin-resistant Staphylococcus aureus isolates in a Chinese teaching hospital from Anhui, China. BMC Microbiol 2012;12:240.
Zhou YN, Lubkowska L, Hui M, Court C, Chen S, Court DL, et al: Isolation and characterization of RNA polymerase rpoB mutations that alter transcription slippage during elongation in Escherichia coli. J Biol Chem 2013;288:2700-2710.
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