Pipeline of anti-Mycobacterium abscessus small molecules: Repurposable drugs and promising novel chemical entities

Abstract

The Mycobacterium abscessus complex is a group of emerging pathogens that are difficult to treat. There are no effective drugs for successful M. abscessus pulmonary infection therapy, and existing drug regimens recommended by the British or the American Thoracic Societies are associated with poor clinical outcomes. Therefore, novel antibacterial drugs are urgently needed to contain this global threat. The current anti-M. abscessus small-molecule drug development process can be enhanced by two parallel strategies-discovery of compounds from new chemical classes and commercial drug repurposing. This review focuses on recent advances in the finding of novel small-molecule agents, and more particularly focuses on the activity, mode of action and structure-activity relationship of promising inhibitors from five different chemical classes-benzimidazoles, indole-2-carboxamides, benzothiazoles, 4-piperidinoles, and oxazolidionones. We further discuss some other interesting small molecules, such as thiacetazone derivatives and benzoboroxoles, that are in the early stages of drug development, and summarize current knowledge about the efficacy of repurposable drugs, such as rifabutin, tedizolid, bedaquiline, and others. We finally review targets of therapeutic interest in M. abscessus that may be worthy of future drug and adjunct therapeutic development.

Keywords: Mycobacterium abscessus; CRS400393; EJMCh-6; IC25; PIPD1; SPR719; delpazolid; early-stage drug development.

Figure 1.

Chemical classes and structures of drugs used in the suggested regimens for adults with Mycobacterium abscessus respiratory infection

Figure 2.

Diversity of M. abscessus drug targets for present and future therapeutic applications, and small molecules acting on them. The most perspective compounds and drugs are marked in red

Figure 3.

Structures, current application fields and approval information of repurposable drugs potentially useful for the treatment of M. abscessus pulmonary infection in future

Figure 4.

Structure-activity relationship of SPR719

Figure 5.

Structure-activity relationships of EJMCh-6

Figure 6.

A) Structure-activity relationships of indole-2-carboxamides, B) Lead indole-2-carboxamides

Figure 7.

Structure-activity relationships of CRS400393

Figure 8.

A) Structure-activity relationships of PIPD1, b) New lead FMD-89

Figure 9.

Structure-activity relationship of delpazolid (LCB01-0371)

Figure 10.

Diversity of other interesting scaffolds for further studies as molecules active against M. abscessus complex

Figure 11.

Pipeline of anti-Mycobacterium abscessus small molecules overview