Fitness‐compensatory mutations in rifampicin‐resistant RNA polymerase

Brandis, Gerrit; Wrande, Marie; Liljas, Lars; Hughes, Diarmaid

doi:10.1111/j.1365-2958.2012.08099.x

Cited by 149 publications

(161 citation statements)

References 49 publications

(76 reference statements)

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“…In the case of rifampicin-induced mutations, for example, which possess identical mutations in rpoB, these data suggest that additional mutations are responsible for transcriptional variation. This likelihood is in accordance with observations from compensatory mutations found in streptomycin-and rifampicin-resistant organisms (18,19), which have been demonstrated to reverse the fitness costs of ribosomal and polymerase mutations. The PCA plots also demonstrate that different antibiotic-induced mutations inducing transcriptional or translational variation can result in apparently similar global changes in metabolism.…”

Section: Analysis Of Changes In Extracted Metabolomes In Antibiotic-rsupporting

confidence: 78%

Antimicrobial drug resistance affects broad changes in metabolomic phenotype in addition to secondary metabolism

Derewacz

Goodwin

McNees

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Bacteria develop resistance to many classes of antibiotics vertically, by engendering mutations in genes encoding transcriptional and translational apparatus. These severe adaptations affect global transcription, translation, and the correspondingly affected metabolism. Here, we characterize metabolome scale changes in transcriptional and translational mutants in a genomically characterized Nocardiopsis, a soil-derived actinomycete, in stationary phase. Analysis of ultra-performance liquid chromatography-ion mobility-mass spectrometry metabolomic features from a cohort of streptomycin-and rifampicin-resistant mutants grown in the absence of antibiotics exhibits clear metabolomic speciation, and loadings analysis catalogs a marked change in metabolic phenotype. Consistent with derepression, up to 311 features are observed in antibiotic-resistant mutants that are not detected in their progenitors. Mutants demonstrate changes in primary metabolism, such as modulation of fatty acid composition and the increased production of the osmoprotectant ectoine, in addition to the presence of abundant emergent potential secondary metabolites. Isolation of three of these metabolites followed by structure elucidation demonstrates them to be an unusual polyketide family with a previously uncharacterized xanthene framework resulting from sequential oxidative carbon skeletal rearrangements. Designated as "mutaxanthenes," this family can be correlated to a type II polyketide gene cluster in the producing organism. Taken together, these data suggest that biosynthetic pathway derepression is a general consequence of some antibiotic resistance mutations.natural products | metabolite discovery | multivariate statistical analysis

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Section: Analysis Of Changes In Extracted Metabolomes In Antibiotic-rsupporting

confidence: 78%

Antimicrobial drug resistance affects broad changes in metabolomic phenotype in addition to secondary metabolism

Derewacz

Goodwin

McNees

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…WGS of isolate MDR-A also revealed two nonsynonymous mutations in the rpoC gene (Gly594Glu and Pro1040Ala). Compensatory mutations in rpoC and rpoA have been previously identified in RIF-resistant isolates (34,35). Although these compensatory mutations seem to be associated mostly with rpoB S531L, a small percentage of rpoB mutants harboring other mutations also present rpoC compensatory mutations.…”

Section: Discussionmentioning

confidence: 99%

Profiling of rpoB Mutations and MICs for Rifampin and Rifabutin in Mycobacterium tuberculosis

et al. 2014

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bResistance to rifampin (RIF) and rifabutin (RFB) in Mycobacterium tuberculosis is associated with mutations within an 81-bp region of the rpoB gene (RIF resistance-determining region [RRDR]). Previous studies have shown that certain mutations in this region are more likely to confer high levels of RIF resistance, while others may be found in phenotypically susceptible isolates. In this study, we sought to determine the relationship between the MICs of RIF and RFB and rpoB RRDR mutations in 32 multidrug-resistant (MDR), 4 RIF-monoresistant, and 5 susceptible M. tuberculosis clinical isolates. The MICs were determined using the MGIT 960 system. Mutations in the rpoB RRDR were determined by Sanger sequencing. RpoB proteins with mutations S531L (a change of S to L at position 531), S531W, H526Y, and H526D and the double mutation D516A-R529Q were associated with high MICs for RIF and RFB. Five isolates carrying the mutations L511P, H526L, H526N, and D516G-S522L were found to be susceptible to RIF. Several mutations were associated with resistance to RIF and susceptibility to RFB (F514FF, D516V, and S522L). Whole-genome sequencing of two MDR isolates without rpoB RRDR mutations revealed a mutation outside the RRDR (V146F; RIF MIC of 50 g/ml). The implications of the polymorphisms identified in the second of these isolates in RIF resistance need to be further explored. Our study further establishes a correlation between the mutations and the MICs of RIF and, also, RFB in M. tuberculosis. Several rpoB mutations were identified in RIF-and RFB-susceptible isolates. The clinical significance of these findings requires further exploration. Until then, a combination of phenotypic and molecular testing is advisable for drug susceptibility testing.

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“…Compensatory mutations can alleviate the loss of fitness produced by drug resistance‐associated mutations (Figure 1b) (Bottger et al., 1998; Brandis, Wrande, Liljas, & Hughes, 2012). In M. tuberculosis, data on compensatory mutations are still limited and mainly focused on isoniazid and rifampicin resistance (Comas et al., 2012; Sherman et al., 1996; Song et al., 2014; de Vos et al., 2013).…”

Section: Compensatory Mutationsmentioning

confidence: 99%

“…These data suggest that mutations in the rpo A/ rpo C genes are fitness‐compensatory mutations that alleviate the costs of rpo B mutations. Furthermore, genetic reconstructions in a Salmonella model demonstrated that mutations not only in rpo A and rpo C, but also in rpo B are associated with higher growth rate (Brandis & Hughes, 2013; Brandis et al., 2012). In fact, many previous studies showed that rifampicin‐resistant M. tuberculosis clinical isolates carry multiple (double, triple and quadruple) mutations in the rpo B gene (Bahrmand, Titov, Tasbiti, Yari, & Graviss, 2009; Casali et al., 2014; Nguyen, Nguyen, et al., 2017; Song et al., 2014).…”

Section: Compensatory Mutationsmentioning

confidence: 99%

“…In fact, many previous studies showed that rifampicin‐resistant M. tuberculosis clinical isolates carry multiple (double, triple and quadruple) mutations in the rpo B gene (Bahrmand, Titov, Tasbiti, Yari, & Graviss, 2009; Casali et al., 2014; Nguyen, Nguyen, et al., 2017; Song et al., 2014). This could be the result of compensatory mechanisms to alleviate the fitness cost exerted by specific mutations (Brandis & Hughes, 2013; Brandis et al., 2012). It is worth noting that compensatory mutations are more commonly identified in the dominant MDR, pre‐XDR and XDR clones in high MDR TB burden countries, suggesting that high drug‐resistant mutants harbouring these mutations can be successfully transmitted in human populations (Casali et al., 2014; Cohen et al., 2015; Comas et al., 2012; Klopper et al., 2013; Li et al., 2016; de Vos et al., 2013).…”

Section: Compensatory Mutationsmentioning

confidence: 99%

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Insights into the processes that drive the evolution of drug resistance in Mycobacterium tuberculosis

Nguyen

Contamin

Nguyen

et al. 2018

Evolutionary Applications

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At present, the successful transmission of drug‐resistant Mycobacterium tuberculosis, including multidrug‐resistant (MDR) and extensively drug‐resistant (XDR) strains, in human populations, threatens tuberculosis control worldwide. Differently from many other bacteria, M. tuberculosis drug resistance is acquired mainly through mutations in specific drug resistance‐associated genes. The panel of mutations is highly diverse, but depends on the affected gene and M. tuberculosis genetic background. The variety of genetic profiles observed in drug‐resistant clinical isolates underlines different evolutionary trajectories towards multiple drug resistance, although some mutation patterns are prominent. This review discusses the intrinsic processes that may influence drug resistance evolution in M. tuberculosis, such as mutation rate, drug resistance‐associated mutations, fitness cost, compensatory mutations and epistasis. This knowledge should help to better predict the risk of emergence of highly resistant M. tuberculosis strains and to develop new tools and strategies to limit the development and spread of MDR and XDR strains.

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Fitness‐compensatory mutations in rifampicin‐resistant RNA polymerase

Cited by 149 publications

References 49 publications

Antimicrobial drug resistance affects broad changes in metabolomic phenotype in addition to secondary metabolism

Antimicrobial drug resistance affects broad changes in metabolomic phenotype in addition to secondary metabolism

Profiling of rpoB Mutations and MICs for Rifampin and Rifabutin in Mycobacterium tuberculosis

Insights into the processes that drive the evolution of drug resistance in Mycobacterium tuberculosis

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