Evolution and Ecology of Drug Resistance

Figure 1: Relative transmission of drug-resistant strains of M. tuberculosis compared to drug-susceptible strains (adapted from Borrell et al. IJTLD 2009).

What is the Origin of Drug Resistance?

One of the most important questions in the epidemiology of drug-resistant TB is whether the global burden of drug resistance is primarily due to the de novo acquisition of resistance during patient treatment or a consequence of transmission of already drug-resistant strains.

Heterogenity in Transmission

Traditionally, the thought was that drug resistance in bacteria was universally associated with a reduction in virulence and/or transmissibility. However, when reviewing the current evidence for the transmissibility of drug-resistant Mtb, we found that multidrug-resistant strains of Mtb were everything from 10 times less- to 10 times more transmissible than drug-susceptible strains (Figure 1).

Compensatory Mutations

The reason for this heterogeneity is partially because the molecular basis of drug resistance in Mtb is complex, and different drug resistance-conferring mutations are associated with different effects on strain fitness. Moreover, by using a combination of experimental evolution, molecular epidemiology and comparative genome sequencing of clinical strains, we identified compensatory mutations in the RNA polymerase which mitigate some of the negative effects associated with rifampicin resistance in Mtb (Figure 2).

These compensatory mutations were associated with increased fitness in vitro and were overrepresented in regions with high burden of multidrug-resistant TB, illustrating some of the bacterial factors that could lead to the observed heterogeneity in transmission of drug-resistant Mtb.

Figure 2: Compensatory mutations in the RNA polymerase of rifampicin-resistant Mtb (adapted from Comas et al. Nat Genet 2012).

Bottazzi P, Winkler M.S, Speranza C.I. Flood governance for resilience in cities: the historical policy transformations in Dakar's suburbs. Environ Sci Policy. 2019(in press). DOI: 10.1016/j.envsci.2018.12.013

Carsin A.E et al. Restrictive spirometry pattern is associated with low physical activity levels. A population based international study. Respir Med. 2019;146:116-123. DOI: 10.1016/j.rmed.2018.11.017

Ghosh R.E et al. Fetal growth, stillbirth, infant mortality and other birth outcomes near UK municipal waste incinerators; retrospective population based cohort and case-control study. Environ Int. 2019;122:151-158. DOI: 10.1016/j.envint.2018.10.060

Jeong J, Obradovic J, Rasheed M, McCoy D.C, Fink G, Yousafzai A.K. Maternal and paternal stimulation: mediators of parenting intervention effects on preschoolers' development. J Appl Dev Psychol. 2019;60:105-118. DOI: 10.1016/j.appdev.2018.12.001

Keitel K. Biomarkers to improve rational antibiotic use in low-resource settings. Lancet Glob Health. 2019;7(1):e14-e15. DOI: 10.1016/S2214-109X(18)30497-2

Laager M et al. A metapopulation model of dog rabies transmission in N'Djamena, Chad. J Theor Biol. 2019;462:408-417. DOI: 10.1016/j.jtbi.2018.11.027

Lee T.E, Penny M.A. Identifying key factors of the transmission dynamics of drug-resistant malaria. J Theor Biol. 2019;462:210-220. DOI: 10.1016/j.jtbi.2018.10.050

Mattli R, Wieser S, Probst-Hensch N, Schmidt-Trucksäss A, Schwenkglenks M. Physical inactivity caused economic burden depends on regional cultural differences. Scand J Med Sci Sports. 2019;29(1):95-104. DOI: 10.1111/sms.13311

Mhimbira F et al. Prevalence and clinical significance of respiratory viruses and bacteria detected in tuberculosis patients compared to household contact controls in Tanzania: a cohort study. Clin Microbiol Infect. 2019;25(1):107 e1-107 e7. DOI: 10.1016/j.cmi.2018.03.019

Mitsakou C et al. Environmental public health risks in European metropolitan areaswithin the EURO-HEALTHY project. Sci Total Environ. 2019;658:1630-1639. DOI: 10.1016/j.scitotenv.2018.12.130