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Review
. 2022 Mar 10;13(4):392-404.
doi: 10.1039/d1md00359c. eCollection 2022 Apr 20.

Potential therapeutic targets from Mycobacterium abscessus (Mab): recently reported efforts towards the discovery of novel antibacterial agents to treat Mab infections

William Addison  1 , Martyn Frederickson  1 , Anthony G Coyne  1 , Chris Abell  1
Affiliations
Review

Potential therapeutic targets from Mycobacterium abscessus (Mab): recently reported efforts towards the discovery of novel antibacterial agents to treat Mab infections

William Addison et al. RSC Med Chem. .

Abstract

Mycobacterium abscessus (Mab) are rapidly growing mycobacteria that cause severe and persistent infections in both skin and lung tissues. Treatment regimens involve the extended usage of complex combinations of drugs, often leading to severe adverse side effects, particularly in immunocompromised patients. Current macrolide therapies are gradually proving to be less effective, largely due to emergence of antibiotic resistance; there is therefore an increasing need for the discovery of new antibacterials that are active against Mab. This review highlights recent research centred upon a number of potential therapeutic targets from Mab (Ag85C, ClpC1, GyrB, MmpL3 and TrmD), and discusses the various approaches used to discover small molecule inhibitors, in the search for future antibiotics for the treatment of Mab infections.

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Conflict of interest statement

There are no conflicts to declare.

Figures

Fig. 1
Fig. 1. Current drugs used against Mycobacterium abscessus infections in cystic fibrosis.
Fig. 2
Fig. 2. Cyclic phosphate based inhibitors of Ag85C from Mycobaterium abscessus.
Fig. 3
Fig. 3. Oxadiazolone based inhibitors of Ag85C from Mycobaterium abscessus.
Fig. 4
Fig. 4. Structure of GSK18 (16), an inhibitor of the ATPase activity of ClpC1.
Fig. 5
Fig. 5. Structures of cyclomarin A (17) and amino derivative (18): inhibitors of ClpC1.
Fig. 6
Fig. 6. Structures of ecumycin (19) and rufomycin derivative (20): inhibitors of ClpC1.
Fig. 7
Fig. 7. Structures of HTS hit (21), clinical candidate (22) and prodrug (23).
Fig. 8
Fig. 8. Pyrroloamide (24): a representative of the class of inhibitors of GyrB.
Fig. 9
Fig. 9. Structures of key inhibitors of MmpL3 from Mtb and Mab.
Fig. 10
Fig. 10. Inhibitors of TrmD from Mycobacterium abscessus discovered using FBDD. The initial fragment hits (30) and (32) were merged to give compound (32) (PDB code: 6QQS). Subsequent elaboration led to the development of compounds (33a) and (33b). X-ray crystal structure is of compound 33a (PDB: 6QR8).
Fig. 11
Fig. 11. Mycobacterium abscessus drug targets discussed in this review and the small molecules acting upon them.
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