Mechanisms of first-line antimicrobial resistance in multi-drug and extensively drug resistant strains of Mycobacterium tuberculosis in KwaZulu-Natal, South Africa

Dookie, Navisha; Sturm, A. Willem; Moodley, Prashini

doi:10.1186/s12879-016-1906-3

Cited by 12 publications

(5 citation statements)

References 24 publications

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“… 31 , 45 , 47 – 51 This was followed by Mycobacterium tuberculosis accounting for 11.3% (n=6) of the reviewed articles. 33 , 34 , 37 , 41 , 42 , 46 Five reviewed articles (9.4%) studied E. coli 40 , 52 , 53 and Enterococcus spp. 30 , 54 – 56 Two different strains of E. coli were also studied, namely E. coli ST131 35 and O157:H7.…”

Section: Resultsmentioning

confidence: 99%

Systematic review in South Africa reveals antibiotic resistance genes shared between clinical and environmental settings

Ekwanzala¹,

Dewar²,

Kamika³

et al. 2018

IDR

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A systematic review was conducted to determine the distribution and prevalence of antibiotic-resistant bacteria (ARB), antimicrobial-resistant genes (ARGs), and antimicrobial-resistant gene determinants (ARGDs) in clinical, environmental, and farm settings and to identify key knowledge gaps in a bid to contain their spread. Fifty-three articles were included. The prevalence of a wide range of antimicrobial-resistant bacteria and their genes was reviewed. Based on the studies reviewed in this systematic review, mutation was found to be the main genetic element investigated. All settings shared 39 ARGs and ARGDs. Despite the fact that ARGs found in clinical settings are present in the environment, in reviewed articles only 12 were found to be shared between environmental and clinical settings; the inclusion of farm settings with these two settings increased this figure to 32. Data extracted from this review revealed farm settings to be one of the main contributors of antibiotic resistance in healthcare settings. ARB, ARGs, and ARGDs were found to be ubiquitous in all settings examined.

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Section: Resultsmentioning

confidence: 99%

Systematic review in South Africa reveals antibiotic resistance genes shared between clinical and environmental settings

Ekwanzala¹,

Dewar²,

Kamika³

et al. 2018

IDR

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“…We hypothesize that these secondary rpoB mutations likely contributed to enhanced transmission and dispersal of KZN/LAM4 via enhanced resistance to rifampin and recovery of overall pathoadaptive fitness versus the L452P single mutant. L452P confers only low-level rifampin resistance, whereas mutations at position 435 (including D435Y and D435G) are associated with distinctly higher rifampin MICs (50), and in LAM4/KZN acquisition of D435G likely augmented rifampin resistance versus the L452P single mutant (51). Recent studies have implicated changes in protein stability (52) and transcriptional efficiency (53) as important determinants of how putative compensatory mutations impact fitness in rifampin-resistant Mtb .…”

Section: Discussionmentioning

confidence: 99%

Pre-detection history of extensively drug-resistant tuberculosis in KwaZulu-Natal, South Africa

Brown

Challagundla

Baugh

et al. 2019

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

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Antimicrobial-resistant (AMR) infections pose a major threat to global public health. Similar to other AMR pathogens, both historical and ongoing drug-resistant tuberculosis (TB) epidemics are characterized by transmission of a limited number of predominant Mycobacterium tuberculosis (Mtb) strains. Understanding how these predominant strains achieve sustained transmission, particularly during the critical period before they are detected via clinical or public health surveillance, can inform strategies for prevention and containment. In this study, we employ whole-genome sequence (WGS) data from TB clinical isolates collected in KwaZulu-Natal, South Africa to examine the pre-detection history of a successful strain of extensively drug-resistant (XDR) TB known as LAM4/KZN, first identified in a widely reported cluster of cases in 2005. We identify marked expansion of this strain concurrent with the onset of the generalized HIV epidemic 12 y prior to 2005, localize its geographic origin to a location in northeastern KwaZulu-Natal ∼400 km away from the site of the 2005 outbreak, and use protein structural modeling to propose a mechanism for how strain-specific rpoB mutations offset fitness costs associated with rifampin resistance in LAM4/KZN. Our findings highlight the importance of HIV coinfection, high preexisting rates of drug-resistant TB, human migration, and pathoadaptive evolution in the emergence and dispersal of this critical public health threat. We propose that integrating whole-genome sequencing into routine public health surveillance can enable the early detection and local containment of AMR pathogens before they achieve widespread dispersal.

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“…In M. tuberculosis , a recent study demonstrated that the rpoB V534M mutation occurred in a clinical outbreak strain and functioned as a compensatory mutation to ameliorate the fitness cost introduced by the primary mutation S450L [ 27 ]. Furthermore, several genome sequencing-based studies demonstrated that many rifampicin-resistant M. tuberculosis clinical isolates carry double/multiple rpoB mutations, with nonsynonymous mutations outside the RRDR commonly co-occurring with RRDR mutations and being more likely to appear in strains without rpoA or rpoC mutations [ 2 , 8 , 28 ], which suggests that these mutations may have a compensatory function.…”

Section: Introductionmentioning

confidence: 99%

Compensatory effects of M. tuberculosis rpoB mutations outside the rifampicin resistance-determining region

Luò

et al. 2021

Emerging Microbes & Infections

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Mycobacterium tuberculosis has been observed to develop resistance to the frontline anti-tuberculosis drug rifampicin, primarily through mutations in the rifampicin resistance-determining region (RRDR) of rpoB. While these mutations have been determined to confer a fitness cost, compensatory mutations in rpoA and rpoC that may enhance the fitness of resistant strains have been demonstrated. Recent genomic studies identified several rpoB non-RRDR mutations that co-occurred with RRDR mutations in clinical isolates without rpoA/rpoC mutations and may confer fitness compensation. In this study, we identified 33 evolutionarily convergent rpoB non-RRDR mutations through phylogenomic analysis of public genomic data for clinical M. tuberculosis isolates. We found that none of these mutations, except V170F and I491F, can cause rifampin resistance in Mycolicibacterium smegmatis. The compensatory effects of five representative mutations across rpoB were evaluated by an in vitro competition assay, through which we observed that each of these mutations can significantly improve the relative fitness of the initial S450L mutant (0.97-1.08 vs 0.87). Furthermore, we observed that the decreased RNAP transcription efficiency introduced by S450L was significantly alleviated by each of the five mutations. Structural analysis indicated that the fitness compensation observed for the non-RRDR mutations might be achieved by modification of the RpoB active centre or by changes in interactions between RNAP subunits. Our results provide experimental evidence supporting that compensatory effects are exerted by several rpoB non-RRDR mutations, which could be utilized as additional molecular markers for predicting the fitness of clinical rifampin-resistant M. tuberculosis strains.

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Mechanisms of first-line antimicrobial resistance in multi-drug and extensively drug resistant strains of Mycobacterium tuberculosis in KwaZulu-Natal, South Africa

Cited by 12 publications

References 24 publications

Systematic review in South Africa reveals antibiotic resistance genes shared between clinical and environmental settings

Systematic review in South Africa reveals antibiotic resistance genes shared between clinical and environmental settings

Pre-detection history of extensively drug-resistant tuberculosis in KwaZulu-Natal, South Africa

Compensatory effects of M. tuberculosis rpoB mutations outside the rifampicin resistance-determining region

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