Why Matter Matters: Fast-Tracking Mycobacterium abscessus Drug Discovery

Abstract

Unlike Tuberculosis (TB), Mycobacterium abscessus lung disease is a highly drug-resistant bacterial infection with no reliable treatment options. De novo M. abscessus drug discovery is urgently needed but is hampered by the bacterium’s extreme drug resistance profile, leaving the current drug pipeline underpopulated. One proposed strategy to accelerate de novo M. abscessus drug discovery is to prioritize screening of advanced TB-active compounds for anti-M. abscessus activity. This approach would take advantage of the greater chance of homologous drug targets between mycobacterial species, increasing hit rates. Furthermore, the screening of compound series with established structure–activity-relationship, pharmacokinetic, and tolerability properties should fast-track the development of in vitro anti-M. abscessus hits into lead compounds with in vivo efficacy. In this review, we evaluated the effectiveness of this strategy by examining the literature. We found several examples where the screening of advanced TB chemical matter resulted in the identification of anti-M. abscessus compounds with in vivo proof-of-concept, effectively populating the M. abscessus drug pipeline with promising new candidates. These reports validate the screening of advanced TB chemical matter as an effective means of fast-tracking M. abscessus drug discovery.

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

“…Unfortunately, the current treatment of MABC infections is very limited due to the extensive drug-resistant profile of this pathogen. As a result, treating these infections requires a lengthy and complex treatment, which is frequently characterized by high failure rates, serious adverse drug effects, and acquired drug resistance ( 7 , 28 , 29 ). Hence, there is an urgent need for novel mycobacterial drug targets and treatment options.…”

“…Moreover, MABC pulmonary disease (MABC-PD) in patients with cystic fibrosis has an estimated prevalence of 13% in Europe and 16% in the US ( 1 ). Infections caused by this complex are known for being very difficult to treat, as MABC is resistant to the standard antimicrobial agents, its treatment displays a low success rate and often leads to adverse drug effects, and various patients experience relapse after treatment or surgical removal of the pathogen ( 2 , 6 , 7 ). Thus, the current treatment of MABC-PD is far from ideal and requires a long-term multidrug therapy including a macrolide together with two to three intravenous drugs during the initial treatment phase or nebulized amikacin and one to four oral drugs during the continuation phase ( 2 ).…”

Exploring antibiotic resistance mechanisms in Mycobacterium abscessus for enhanced therapeutic approaches

“…Repurposing previously approved pharmaceuticals can expedite the development process and reduce expenses ( Egorova et al, 2021 ). Regrettably, the Mab drug pipeline remains underpopulated ( Ganapathy and Dick, 2022 ). Currently, there are four recruiting, four completed, one terminated, and two non-recruiting clinical trials evaluating drug efficacy in Mab infection ( NIH ClinicalTrials, 2023 ).…”

Mycobactin analogue interacting with siderophore efflux-pump protein: insights from molecular dynamics simulations and whole-cell assays

“…This rapidly emerging resistance has dire consequences with reports indicating that an estimated 700,000 deaths every year can be attributed to antimicrobial resistance (AMR), which is projected to reach a staggering 10.5 million per year by 2050 (O'Neill, 2014). A significant proportion of AMR mortality (27%) is attributable to Mycobacterium tuberculosis (Mtb)-caused by drug-resistant tuberculosis (DR-TB) (WHO, 2023) whereas Mycobacterium abscessus, a fast-growing non-tubercular mycobacterium (NTM), from the same acenatobactor family is becoming increasingly prevalent, particularly in individuals with congenital lung disorders such as cystic fibrosis (Johansen et al, 2020;Ganapathy and Dick, 2022).…”