Fitness Cost and Compensatory Evolution in Levofloxacin-Resistant
            <i>Mycobacterium aurum</i>

Pi, Rui; Liu, Qingyun; Takiff, Howard; Gao, Qian

doi:10.1128/aac.00224-20

Cited by 10 publications

(7 citation statements)

References 14 publications

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“…The lack of corelation between the magnitude of resistance and the proportion of a population containing a minor resistance conferring allele (Figure 2a-d) is consistent with the suggestion that gyrA D94G and A90V do not contribute a significant fitness cost 15 .…”

Section: Discussionsupporting

confidence: 85%

Inclusion of minor alleles improves catalogue-based prediction of fluoroquinolone resistance inMycobacterium tuberculosis

Brankin

Fowler

2022

Preprint

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Fluoroquinolone resistance poses a threat to the successful treatment of tuberculosis. Whole genome sequencing (WGS), and the subsequent detection of catalogued resistance- associated mutations, offers an attractive solution to fluoroquinolone susceptibility testing. However, the bioinformatic pipelines used often mask the recognition of minor alleles which are implicated in fluoroquinolone resistance. Using the Comprehensive Resistance Prediction for Tuberculosis: an International Consortium's (CRyPTIC) dataset of globally diverse WGS Mycobacterium tuberculosis isolates, with matched minimum inhibitory concentrations for two fluoroquinolone drugs, we show that detecting minor alleles increased the sensitivity of WGS for moxifloxacin resistance prediction from 85.4% to 94.0%, without significantly reducing specificity. We also found no correlation between the proportion of an M. tuberculosis population containing a resistance-conferring allele and the magnitude of resistance. Together our results highlight the importance of detecting minor resistance conferring alleles when using WGS, or indeed any sequencing-based approach, to diagnose fluoroquinolone resistance.

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Section: Discussionsupporting

confidence: 85%

Inclusion of minor alleles improves catalogue-based prediction of fluoroquinolone resistance inMycobacterium tuberculosis

Brankin

Fowler

2022

Preprint

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“…Antibiotic resistance usually causes bacterial growth defects or weakened virulence, called fitness costs, owing to production and maintenance of resistance machinery (Wang et al, 2019;Pi et al, 2020;Balbontín et al, 2021). Susceptible bacterial populations usually outcompete resistant ones in the absence of antibiotics because of the fitness cost (Pacheco et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…Gyrase is a heterotetramer comprising two GyrA and two GyrB subunits, catalyzing a DNA double-strand break, passing another DNA strand through the break, and resealing it (Hooper and Jacoby, 2015). Mutations in gyrA and gyrB, known as quinoloneresistance-determining regions, can cause bacterial resistance to LVX (Pi et al, 2020). The SNP and InDel analyses based on WGS showed that one nonsynonymous SNP and one InDel mutations occurred in gyrB (PA0004) and gyrA (PA3168) of the PAS81 strain, respectively.…”

Section: Discussionmentioning

confidence: 99%

Pseudomonas aeruginosa heteroresistance to levofloxacin caused by upregulated expression of essential genes for DNA replication and repair

Zhang

Liao

et al. 2022

Front. Microbiol.

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Pseudomonas aeruginosa (P. aeruginosa), a common cause of severe chronic infections, has developed heteroresistance to several antibiotics, thus hindering successful treatment. In this study, we aimed to investigate the characteristics and mechanisms underlying levofloxacin (LVX) heteroresistance in P. aeruginosa PAS71 and PAS81 clinical isolates using a combination of physiological and biochemical methods, bacterial genomics, transcriptomics, and qRT-PCR. The six P. aeruginosa strains, namely PAS71, PAS72, PAS81, PAS82, ATCC27853, and PAO1, were studied. The Kirby–Bauer (K–B), minimum inhibitory concentration (MIC) test, and population analysis profile (PAP) experimental results showed that PAS71, PAS81, ATCC27853, and PAO1 were heteroresistant to LVX, with MIC of 0.25, 1, 0.5, and 2 μg/ml, respectively; PAS72 and PAS82 were susceptible to LVX with a MIC of 0.25 and 0.5 μg/ml, respectively. The resistance of PAS71 and PAS81 heteroresistant subpopulations was unstable and had a growth fitness cost. Genomic and transcriptomic results proved that the unstable heteroresistance of PAS71 and PAS81 was caused by elevated expression of essential genes involved in DNA replication and repair, and homologous recombination, rather than their genomic single-nucleotide polymorphism (SNP) and insertion–deletion (InDel) mutations. Additionally, PAS71 and PAS81 enhanced virulence and physiological metabolism, including bacterial secretion systems and biosynthesis of siderophore group nonribosomal peptides, in response to LVX stress. Our results suggest that the upregulation of key genes involved in DNA replication and repair, and homologous recombination causes unstable heteroresistance in P. aeruginosa against LVX. This finding provides novel insights into the occurrence and molecular regulation pathway of P. aeruginosa heteroresistant strains.

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“…Rifampin (RIF) rpoB rpoA, rpoC (Telenti et al, 1993;Ohno et al, 1996;Ramaswamy and Musser, 1998;Comas et al, 2011;Shea et al, 2021) Pyrazinamide (PZA) pncA pnaB2 (epistatic) (Konno et al, 1967;Scorpio and Zhang, 1996;Muzondiwa et al, 2021) Para-aminosalicylic acid (PAS) thyA thyX-hsdS.1 intergenic region associated, but not shown to be compensatory (Rengarajan et al, 2004;Zhang et al, 2013;Coll et al, 2018) Ethambutol (EMB) embCAB operon aftA (Rv3792) (Alcaide et al, 1997;Telenti et al, 1997;Safi et al, 2013) Isoniazid (INH) katG, inhA ahpC promoter (Zhang et al, 1992;Heym et al, 1995;Sherman et al, 1996) Fluoroquinolones (FQ) gyrA Extragenic Rv0890c, Insertions in glgC in Mycobacterium aurum (Takiff et al, 1994;Pi et al, 2020) Bedaquiline (BDQ) mmpR (Rv0678), atpE, pepQ atpB? (suggested) (Andries et al, 2005;de Jonge et al, 2007;Huitric et al, 2010;Andries et al, 2014;Nieto Ramirez et al, 2020) Clofazimine (CFZ) pepQ, mmpR Unknown (Almeida et al, 2016) Pretomanid (PA-824)/ Delaminid (DLM)…”

Section: Compensatory Mechanism Referencesmentioning

confidence: 99%

The evolving biology of Mycobacterium tuberculosis drug resistance

Jones

Adams

Eldesouky

et al. 2022

Front. Cell. Infect. Microbiol.

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Tuberculosis, caused by Mycobacterium tuberculosis (Mtb) is an ancient disease that has remained a leading cause of infectious death. Mtb has evolved drug resistance to every antibiotic regimen ever introduced, greatly complicating treatment, lowering rates of cure and menacing TB control in parts of the world. As technology has advanced, our understanding of antimicrobial resistance has improved, and our models of the phenomenon have evolved. In this review, we focus on recent research progress that supports an updated model for the evolution of drug resistance in Mtb. We highlight the contribution of drug tolerance on the path to resistance, and the influence of heterogeneity on tolerance. Resistance is likely to remain an issue for as long as drugs are needed to treat TB. However, with technology driving new insights and careful management of newly developed resources, antimicrobial resistance need not continue to threaten global progress against TB, as it has done for decades.

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Fitness Cost and Compensatory Evolution in Levofloxacin-Resistant Mycobacterium aurum

Cited by 10 publications

References 14 publications

Inclusion of minor alleles improves catalogue-based prediction of fluoroquinolone resistance inMycobacterium tuberculosis

Inclusion of minor alleles improves catalogue-based prediction of fluoroquinolone resistance inMycobacterium tuberculosis

Pseudomonas aeruginosa heteroresistance to levofloxacin caused by upregulated expression of essential genes for DNA replication and repair

The evolving biology of Mycobacterium tuberculosis drug resistance

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