The 2016 JA Medal for an original article is awarded for an excellent paper entitled 'Discovery of a capuramycin analog that kills nonreplicating Mycobacterium tuberculosis and its synergistic effects with translocase I inhibitors' by Shajila Siricilla, Katsuhiko Mitachi, Bajoie Wan, Scott G Franzblan and Michio Kurosu1 from University of Tennessee Health Science Center, Memphis and University of Illinois at Chicago, Chicago, IL, USA.
Current serious problems for tuberculosis (TB) control are long-term chemotherapy due to the nonreplicating (dormant) state of Mycobacterium tuberculosis (Mtb) and the occurrence of extensively drug resistant Mtb. The authors studied structure-activity relationships of capuramycin, a known inhibitor of translocase I (MurX/MreY or MurX for Mtb translocase I), involved in cell wall peptidoglycan biosynthesis. In this work, UT-01320, a synthetic 2′-methylated capuramycin analog, was found to kill both replicating and nonreplicating Mtb at low concentrations in in vitro assays. Surprisingly, UT-01320 does not inhibit MurX activity but potently blocks bacterial RNA polymerases, indicating that O-methylation at 2′ position alters its molecular target. Furthermore, UT-01320 displayed strong synergistic effects with MurX inhibitors such as capuromycin and the capuromycin analog SQ641, a preclinical drug. This work demonstrated a new type of bacterial RNA polymerase inhibitors targeting the dormant form of Mtb, leading to a promising TB chemotherapy. This paper also emphasizes the important concept that small change in antibiotic structure can result in significant impact on mode of action.
The 2016 JA Medal for reviews goes to an outstanding article entitled 'Glycopeptide antibiotic biosynthesis' by Gerard Wright and colleagues.2 In this article, the authors report the current state of our knowledge of the biosynthesis of glycopeptide antibiotics (GPAs) such as vancomycin, the founding member of this class. GPAs are frequently used as a 'last resort' antibiotic treatment for many infections by Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus. However, the emergence of vancomycin-resistant enterococci (VRE) and its global spread as glycopeptide-resistant enterococci (GRE) have become a serious threat to the clinical community that has increasingly relied on GPAs to cure infectious disease, as a limited number of new antibiotics are in the pipeline. Exploration of GPA biosynthesis and elucidation of the resistance mechanism are key to achieving the goal of overcoming resistance with genetically and/or chemically modified GPAs.
The large and intricate chemical structures of GPAs consist of highly crosslinked and diversely modified core heptapeptides, synthesized by nonribosomal peptide synthetases (NRPS) and a variety of modification enzymes responsible for oxidative crosslinking, glycosylation, acylation, chlorination, sulfation, and methylation. This JA Medal winning group comprehensively describes detailed characterization of biosynthetic gene clusters revealed by whole-genome or meta-genome sequencing and the mechanism of self-resistance in producing microorganisms. Producers and other resistant organisms alter the target pentapeptide in Lipid II to terminate in D-Ala-D-Lactate rather than the canonical D-Ala-D-Ala, which reduces the affinity of GPAs by 1000-fold. Further understanding of both the biosynthesis of and resistance to GPAs will provide profound insights into strategies for the development of the next generation of GPAs to fight against GRE.