Infectious tuberculosis (TB) is often caused by the intracellular pathogenic bacillus Mycobacterium tuberculosis (Mtb). TB continues to be a global burden that is becoming increasingly more difficult to treat with antibiotic agents. Multi drug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) forms of TB are becoming more prevalent in the clinic which require the use of second and third-line antibiotics to treat and cure the pathology. In order to treat MDR- and XDR-TB patients, phenothiazines, which have been shown to have in-vitro activity against Mtb,[1] have been suggested for use because of their novel mechanism of action against type II- NADH:menaquinone oxidoreductase in Mtb[2] as well as other potential targets.[3] However, these neuroleptic agents have been avoided by clinicians due to side effects affecting the central nervous system.[4] These drugs, much like the FDA-approved D-cycloserine (DCS), can be effective anti-tubercular agents but can present vicious side-effects with long-term treatments. To circumvent these issues, we have devised a targeting strategy to deliver these anti-tubercular agents directly and selectively to Mtb. With a b-lactam promoiety, we can utilize a germline-encoded b-lactamase, b-Lactamase C (BlaC), with broad specificity and a very large binding pocket. This enzyme can facilitate delivery of these drugs to Mtb without exposure to brain tissue and commensal organisms. Herein we describe conjugates of DCS and other neuroleptic agents which are modified cephalosporins and cephamycins that lack antibacterial activity on their own[5], are stable in serum, and display specificity for BlaC.[6] [1] Viveiros, M.; et. al. Int. J. Antimicrobial Agents, 2000, 16, 69 [2] Weinstein, E. A.; et. al. Proc. Nat. Acad. Sci. USA 2005, 102, 4548 [3] Amelia, M. et. al. Int. J. Antimicrobial Agents, 2003, 22, 347 [4] Amaral, L. et. al. Int. J. Antimicrobial Agents, 2010, 35, 524 [5] Xie, H.; et. al. Nat. Chem. 2012, 4, 802 [6] Cheng, Y.;et. al. Angew. Chem. Int. Ed. 2014, 53, 9360

Keeping antibiotics off your mind: Beta-lactam conjugates of D-cycloserine and other neuroleptic agents effective against Mycobacterium tuberculosis

251st National Meeting (2016)

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