Mycothione reductase as a potential target in the fight against Mycobacterium abscessus infections

Abstract

ABSTRACT While infections caused by Mycobacterium abscessus complex (MABC) are rising worldwide, the current treatment of these infections is far from ideal due to its numerous shortcomings thereby increasing the urge for novel drug targets. In this study, mycothione reductase (Mtr) was evaluated for its potential as a drug target for MABC infections since it is a key enzyme needed in the recycling of mycothiol, the main low-molecular-weight thiol protecting the bacteria against reactive oxygen species and other reactive intermediates. First, a Mab ∆ mtr mutant strain was generated, lacking mtr expression. Next, the in vitro sensitivity of Mab ∆ mtr to oxidative stress and antimycobacterial drugs was determined. Finally, we evaluated the intramacrophage survival and the virulence of Mab ∆ mtr in Galleria mellonella larvae. Mab ∆ mtr demonstrated a 39.5-fold reduction in IC90 when exposed to bedaquiline in vitro . Furthermore, the Mab ∆ mtr mutant showed a decreased ability to proliferate inside macrophages and larvae, suggesting that Mtr plays an important role during MABC infection. Altogether, these findings support the assumption of Mtr being a potential target for antimycobacterial drugs. IMPORTANCE Mycobacterium abscessus complex (MABC) is a group of bacteria causing a serious public health problem worldwide due to its ability to cause progressive disease, its highly resistant profile against various antibiotics, and its lengthy treatment. Therefore, new drugs are needed to alleviate antibiotic resistance and reduce the length of the current treatment. A potential new target for new antibiotics is mycothione reductase (Mtr), an important enzyme belonging to a pathway that protects the bacteria against harmful conditions. Our research created a bacterium deficient of mtr by using advanced genetic techniques and demonstrated that mtr -deficient bacteria have a decreased ability to multiply during infection. Furthermore, we show evidence that currently used antibiotics combined with mtr deficiency can lead to a better treatment of MABC infection. Altogether, our results validate Mtr as a potential new target and suggest that Mtr plays a role during MABC infection.