β-Lactam antibiotics, such as penicillins, cephalosporins, monobactams, and carbapenems, have long been a treatment of choice for bacterial infections. They bind irreversibly to Penicillin-Binding Proteins (PBPs), which catalyse the biosynthesis of the bacterial cell wall, eventually resulting in cell death. The continuing and increasing problem of resistance to β-lactam antibiotics due to β-lactamases has motivated work toward the identification of new classes of PBP inhibitors to combat these resistant bacteria. One approach involves the use of appropriately functionalized electrophiles (sometimes referred to as transition state analogues) that is able to react reversibly with the nucleophilic active site serine of the PBPs. Due to the reversible nature of their interactions with PBPs, this new class of PBP inhibitors are non-hydrolyzable, and hence not susceptible to β-lactamases resistance.
We have identified some of the most potent, non-β-lactam, boronic acid-based PBP inhibitors that are active against common pathogens, including the notorious methicillin-resistant Staph. aureus (MRSA). This work also demonstrates the potential of boronate-based PBP inhibitors for circumventing β-lactam resistance, and opens avenues for the development of novel antibiotics that target Gram-positive pathogens. Through this work, detailed structural information on PBP and β-lactamases is now available, and a challenge will be to use this to achieve the breadth of selectivity and potency required for clinically useful antibiotics.
- Singh, N.: challiday, A.; Thomas, J.; Kuznetsova, O.; Baldwin, R.; Woon, E. C. Y.; Aley, P.; Antoniadou, I.; Sharp, T.; Vasudevan, S.; Churchill, G.A safe lithium mimetic for bipolar disorder. Nature Communications, 2013, 4, article no. 1332, doi:10.1038/ncomms2320.
- Chowdhury, R.; Yeoh, K. K.; Tian, Y. M.; Hillringhaus, L.; Bagg, E. A.; Rose, N. R.; Leung, I. K. H.; Li, X. S.; Woon, E. C. Y.; Yang, M.; et. al. The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. EMBO reports, 2011, 12, 463-469.
- Rose, N. R.; Woon, E. C. Y.; Kingham, G. L.; King, O. N. F.; et.al. Selective inhibitors of the JMJD2 histone demethylases: combined nondenaturing mass spectrometric screening and crystallographic approaches. Journal of Medicinal Chemistry 2010, 53, 1810‑1818.
- Woon, E. C. Y.; Demetriades, M.; Bagg, E. A. L. et. al. Dynamic combinatorial mass spectrometry leads to inhibitors of a 2‑oxoglutarate dependent nucleic acid demethylase. Journal of Medicinal Chemistry 2012, 55, 2173-2184.