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Project

Investigating the mechanisms of drug persistence in Nontuberculous Mycobacteria and its impact on the emergence of resistance

Nontuberculous mycobacteria (NTM) can cause severe pulmonary diseases (NTM-PD) in humans. As NTM are opportunistic, environmental bacteria present in soil, waterbodies but also showerheads, exposure to NTM is high. While the risk of infection is low, the infection rate is high in immunocompromised patients and patients with pre-existing lung conditions Prevalence of NTM infections is increasing worldwide. Current treatment of NTM-PD encompasses a 3-4 drug cocktail of Mtb drugs. This treatment is very long and is generally associated with low efficacy, high toxicity and significant financial burden. The limited and largely ineffective anti-NTM drugs available on the market make NTM-PD patients extremely vulnerable to the emergence of drug-resistance species, rendering existing drugs even less effective. Furthermore, the severe side effects of existing drugs result in patient noncompliance, which is in turn a driver for NTM acquiring antibiotic resistance. Importantly, other than acquired resistance, NTM can take advantage of an innate strategy to evade antibiotic action by becoming persistent. Persisters are genetically identical, phenotypic variants within a susceptible population that transiently tolerate lethal doses of antibiotics. Although the persister phenotype is non-inheritable, genetic mutations can affect the fraction of persister cells in a population. The latter is the case with high persister (hip) mutants that have a higher persister fraction. However, hip mutations do not confer resistance (via target modification or other mechanism, such as drug efflux). Hip mutations have emerged in longitudinal isolates of chronic infections in Escherichia coli, Pseudomonas aeruginosa, Salmonella and Mtb species and the presence of persistent bacteria results in longer treatments. In addition, both clinical and in vitro studies support a role for tolerant and persister cells in the emergence of genotypic antibiotic resistance. This has is yet to be proven in NTM. This joint project between VIB-KU Leuven and Janssen aims to explore the mechanisms of persister formation in NTM, the role of persisters in drug resistance and identify potential new druggable targets that are involved in drug persistence of NTM. Ultimately, this will identify new potential strategies to treat NTM infection, while minimizing the risk of acquiring drug resistance in NTM.

Date:1 Sep 2020 →  Today
Keywords:nontuberculous mycobacteria, Mycobacterium abscessus, persistence, resistance, hip mutations
Disciplines:Bacteriology
Project type:PhD project