Deep resequencing of serial sputum isolates of Mycobacterium tuberculosis during therapeutic failure due to poor compliance reveals stepwise mutation of key resistance genes on an otherwise stable genetic background

Saunders, N.; Trivedi, Urmi; Thomson, Marian; Doig, Christine; Laurenson, Ian F.; Blaxter, Mark

doi:10.1016/j.jinf.2011.01.003

Cited by 53 publications

(48 citation statements)

References 29 publications

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“…Thus, the genome of M. bovis, and presumably that of M. tuberculosis, may be exceptionally stable. Such a conclusion for M. tuberculosis is supported by (i) the paucity of synonymous (silent) mutations in structural genes (40,41,57) and (ii) the failure of sequential isolates obtained during the development of MDR TB to show mutations other than those in the resistance genes (53).…”

Section: Discussionmentioning

confidence: 99%

Induction of Mycobacterial Resistance to Quinolone Class Antimicrobials

Malik¹,

Chavda²,

Zhao

et al. 2012

Antimicrob Agents Chemother

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ABSTRACTAn agar plate assay was developed for detecting the induction of drug-resistant mycobacterial mutants during exposure to inhibitors of DNA gyrase. WhenMycobacterium smegmatison drug-containing agar, resistant colonies arose over a period of 2 weeks. ArecAdeficiency reduced mutant recovery, consistent with involvement of the SOS response in mutant induction. The C-8-methoxy compounds gatifloxacin and moxifloxacin allowed the recovery of fewer resistant mutants than either ciprofloxacin or levofloxacin when present at the same multiple of the MIC; a quinolone-like 8-methoxy-quinazoline-2,4-dione was more effective at restricting the emergence of resistant mutants than its cognate fluoroquinolone. Thus, the structure of fluoroquinolone-like compounds affects mutant recovery. A spontaneous mutator mutant ofM. smegmatis, obtained by growth in medium containing both isoniazid and rifampin, increased mutant induction during exposure to ciprofloxacin. Moreover, the mutator increased the size of spontaneous resistant mutant subpopulations, as detected by population analysis. Induction of ciprofloxacin resistance was also observed withMycobacterium tuberculosisH37Rv. When measured with clinical isolates, no difference in mutant recovery was observed between multidrug-resistant (MDR) and pansusceptible isolates. This finding is consistent with at least some MDR isolates ofM. tuberculosislacking mutators detectable by the agar plate assay. Collectively, the data indicate that the use of fluoroquinolones against tuberculosis may induce resistance and that the choice of quinolone may be important for restricting the recovery of induced mutants.

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Section: Discussionmentioning

confidence: 99%

Induction of Mycobacterial Resistance to Quinolone Class Antimicrobials

Malik¹,

Chavda²,

Zhao

et al. 2012

Antimicrob Agents Chemother

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“…The ability to sequence entire bacterial genomes has afforded the opportunity to sequence in vitro and in vivo evolved drug-resistant isolates, along with their susceptible ancestors, to identify mutations associated with resistance (Mwangi et al 2007;Arias et al 2011;Howden et al 2011;Saunders et al 2011). Strikingly, several studies have noted that the most prevalent resistance genotypes are those associated with the lowest fitness cost (Mwangi et al 2007), pointing to the long-term instability of high-cost mutations in the absence of compensatory mutations (Gagneux et al 2006;Comas et al 2012;Nielsen et al 2012).…”

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confidence: 99%

Genomic insights into the fate of colistin resistance and Acinetobacter baumannii during patient treatment

et al. 2013

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Bacterial whole-genome sequencing (WGS) of human pathogens has provided unprecedented insights into the evolution of antibiotic resistance. Most studies have focused on identification of resistance mutations, leaving one to speculate on the fate of these mutants once the antibiotic selective pressure is removed. We performed WGS on longitudinal isolates of Acinetobacter baumannii from patients undergoing colistin treatment, and upon subsequent drug withdrawal. In each of the four patients, colistin resistance evolved via mutations at the pmr locus. Upon colistin withdrawal, an ancestral susceptible strain outcompeted resistant isolates in three of the four cases. In the final case, resistance was also lost, but by a compensatory inactivating mutation in the transcriptional regulator of the pmr locus. Notably, this inactivating mutation reduced the probability of reacquiring colistin resistance when subsequently challenged in vitro. On face value, these results supported an in vivo fitness cost preventing the evolution of stable colistin resistance. However, more careful analysis of WGS data identified genomic evidence for stable colistin resistance undetected by clinical microbiological assays. Transcriptional studies validated this genomic hypothesis, showing increased pmr expression of the initial isolate. Moreover, altering the environmental growth conditions of the clinical assay recapitulated the classification as colistin resistant. Additional targeted sequencing revealed that this isolate evolved undetected in a patient undergoing colistin treatment, and was then transmitted to other hospitalized patients, further demonstrating its stability in the absence of colistin. This study provides a unique window into mutational pathways taken in response to antibiotic pressure in vivo, and demonstrates the potential for genome sequence data to predict resistance phenotypes.

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“…These restricting factors significantly limit NGS technologies for POC testing according to the ASSURED criteria (Affordable, Sensitive, Specific, User friendly, Reliable and robust, Equipment-free and Deliverable to those who need it) recommended by the WHO [89]. Nevertheless, NGS at a centralized facility have assisted researchers in identifying mutations conferring resistance to Mtb [90] and other infections. Future successes in developing reliable assays for POC detection of DR-TB could benefit from further refinement of nano/micro-technologies to reduce cost and increase clinical utility, as well as from biomarker discovery by high throughput sequencing technologies.…”

Section: Discussionmentioning

confidence: 99%

Emerging technologies for monitoring drug-resistant tuberculosis at the point-of-care

Mani

Wang

İnci

et al. 2014

Advanced Drug Delivery Reviews

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Infectious diseases are the leading cause of death worldwide. Among them, tuberculosis (TB) remains a major threat to public health, exacerbated by the emergence of multiple drug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis (Mtb). MDR-Mtb strains are resistant to first-line anti-TB drugs such as isoniazid and rifampicin; whereas XDR-Mtb strains are resistant to additional drugs including at least to any fluoroquinolone and at least one of the second-line anti-TB injectable drugs such as kanamycin, capreomycin, or amikacin. Clinically, these strains have significantly impacted the management of TB in high-incidence developing countries, where systemic surveillance of TB drug resistance is lacking. For effective management of TB on-site, early detection of drug resistance is critical to initiate treatment, to reduce mortality, and to thwart drug-resistant TB transmission. In this review, we discuss the diagnostic challenges to detect drug-resistant TB at the point-of-care (POC). Moreover, we present the latest advances in nano/microscale technologies that can potentially detect TB drug resistance to improve on-site patient care.

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Deep resequencing of serial sputum isolates of Mycobacterium tuberculosis during therapeutic failure due to poor compliance reveals stepwise mutation of key resistance genes on an otherwise stable genetic background

Cited by 53 publications

References 29 publications

Induction of Mycobacterial Resistance to Quinolone Class Antimicrobials

Induction of Mycobacterial Resistance to Quinolone Class Antimicrobials

Genomic insights into the fate of colistin resistance and Acinetobacter baumannii during patient treatment

Emerging technologies for monitoring drug-resistant tuberculosis at the point-of-care

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