The rise of infections caused by multidrug-resistant (MDR) bacterial pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA) and extended-spectrum �-lactamase (ESBL)-producing enterobacteriaceae, has created an acute need for new antibiotics with novel mechanisms of action.  The essential role that FtsZ plays in bacterial cell division makes it an attractive new antibiotic target that is not exploited by any current clinical agent.  Methoxybenzamides represent a promising class of FtsZ-directed agents for the treatment of staphylococcal infections.  However, their development as potentially useful clinical agents has been hampered by problems related to (i) drugability, (ii) frequency of resistance (FOR), and (iii) spectrum of activity.  This presentation will focus on our approach to addressing each of these problems.  We have developed Mannich base and carboximide derivatives with enhanced drugable properties and both oral and intravenous efficacy in vivo [1,2].  In addition, we have determined that the spectrum of activity of methoxybenzamide derivatives can be extended to include Gram-negative pathogens through concomitant efflux pump inhibition [3].  [1]     M. Kaul, L. Mark, Y. Zhang, A.K. Parhi, E.J. LaVoie, D.S. Pilch, Pharmacokinetics and In Vivo Antistaphylococcal Efficacy of TXY541, a 1-Methylpiperidine-4-Carboxamide Prodrug of PC190723, Biochem. Pharmacol. 86 (2013) 1699-16707.[2]     M. Kaul, L. Mark, Y. Zhang, A.K. Parhi, E.J. LaVoie, D.S. Pilch, An FtsZ-Targeting Prodrug with Oral Antistaphylococcal Efficacy In Vivo, Antimicrob. Agents Chemother. 57 (2013) 5860-5869.[3]     M. Kaul, Y. Zhang, A.K. Parhi, E.J. LaVoie, D.S. Pilch, Inhibition of RND-Type Efflux Pumps Confers the FtsZ-Directed Prodrug TXY436 with Activity Against Gram-Negative Bacteria, Biochem. Pharmacol. (2014) doi 10.1016/j.bcp.2014.03.002.

Enhancing the efficacy of FtsZ-directed methoxybenzamides vs. staphylococcal infections and extending their activity to include Gram-negative pathogens

248th National Meeting (2014)

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