DNA ligases join adjacent 3Ј-hydroxyl and 5Ј-phosphoryl termini to form a phosphodiester bond in duplex DNA (22,38). DNA ligases function in DNA replication, by joining Okazaki fragments on the lagging strand of DNA, and are involved in several DNA repair pathways (e.g., nucleotide excision repair). DNA ligation proceeds in three nucleotidyl transfer steps. The first step involves the formation of a covalent DNA ligase-adenylate intermediate. In the second step, AMP is transferred from DNA ligase to the 5Ј phosphate of nicked DNA through a pyrophosphate bond. In the third step, a phosphodiester bond is formed to join adjacent polynucleotides, and AMP is released (22,38).

Background: A search was initiated to identify inhibitors of the acetyltransferase domain of GlmU that could be exploited as starting points for new antimicrobials. Results: Sulfonamide inhibitors were identified that upon chemical modification displayed antimicrobial activity mediated via GlmU. Conclusion: Enzymatic inhibition of GlmU can lead to antimicrobial activity. Significance: For the first time, GlmU was validated as an antimicrobial target in vitro.

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The prospect of ever increasing antibiotic resistance eroding currently available treatment options for bacterial infections underscores the need to continue to identify new antibiotics, preferably those that act on novel targets or with novel mechanisms of action. Bacterial gyrase B subunit (GyrB), an essential component of bacterial gyrase required for successful DNA replication, represents such a target. We describe recent examples of GyrB inhibitors and point out their potential utility for treatment of mycobacterial diseases caused by Mycobacterium tuberculosis (TB) and non-tuberculous mycobacteria (NTM). Current therapeutic options for these diseases are often suboptimal due to resistance to current standard of care antibiotics. A future GyrB inhibitor-based antibiotic could offer a new and effective addition to the armamentarium for treatment of mycobacterial diseases and possibly for infections caused by other bacterial pathogens. One GyrB inhibitor, SPR720, has recently completed a first-in-human clinical trial and is in clinical development for the treatment of NTM and TB infections.

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