Investigating Mtr and MshC as potential targets in the fight against Mycobacterium abscessus infections
Mycobacterium abscessus complex (MABC) infections have been increasing worldwide over the last two decades, leading to a higher morbidity and mortality associated with this pathogen. Treatment of MABC infections remains a challenge due to the highly resistant nature of MABC to various antibiotics together with a suboptimal treatment that demonstrates a lengthy multidrug therapy for 18 to 24 months, severe adverse drug effects and a treatment success rate of only 45.6%. To improve MABC treatment and avoid the further development of drug resistance, novel anti-MABC targets need to be explored. An interesting novel anti-MABC target is the mycothiol (MSH) biosynthesis and recycling pathway, since MSH acts as an antioxidant for the neutralization of reactive oxygen and nitrogen species. To tackle both the biosynthesis and recycling pathway of MSH, one enzyme of each pathway was selected as a potential target, cysteine ligase (MshC) and mycothione reductase (Mtr) respectively. This study employed a target-based drug discovery approach for the investigation of MshC and Mtr as potential novel targets for anti-MABC drugs. Hereby, various genetic engineering tools were employed to manipulate the genome of one of the subspecies of MABC, M. abscessus abscessus (Mab), and create mshC and mtr overexpressing, knockdown and knockout strains. These strains were then subjected to a variety of conditions to evaluate the role and protective function of mshC and mtr during oxidative stress and infection. Based on the obtained results, this study demonstrated that the overexpression of mshC or mtr is not advantageous for Mab during stress conditions nor infection. Furthermore, the successful generation of a mtr knockout strain indicated that mtr is not essential for the overall survival of Mab, however, was shown to be conditionally essential for the proliferation of Mab during infection. Finally, as MABC treatment always requires a multidrug therapy and our findings indicated that the inhibition of mtr may work synergistically with other anti-MABC drugs, Mtr was established as a promising target for use in combination with the current MABC treatment.
Antwerp : University of Antwerp, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, Department of Pharmaceutical Sciences , 2024
218 p.
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Creation 17.04.2024
Last edited 18.04.2024
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