Antibiotic resistance among common bacterial pathogens is a serious public health problem as it compromises our ability to treat infectious disease. The resistance problem is compounded by the lack of discovery of new antibiotics, especially those with novel mechanisms of action. New antibiotics are critically needed as resistance to recently developed antibiotics is growing. The goal of this project is to develop our triazolononactate antibiotics, as exemplified by our lead compound PBI31G12, as broad spectrum agents active against Gram positive pathogens. Specifically we will improve the antibacterial activity and selectivity of our current lead compounds against S. aureus (including MRSA), E. faecalis (including VRE) and S. pyogenes. We will obtain data that will allow us to make a hypothesis concerning the MOA of the triazolononactate compound class and to identify the target so that we may employ structure-based drug design to achieve our goals of potency and spectrum of activity. In addition to using classic tracer studies we will use several resistant bacterial strains in hand to determine the genetic modifications leading to resistance. Beyond the improvement of potency and identification of the cellular target we will initiate DMPK studies to determine if the triazolononactate compound class has any critical liabilities such as metabolic instability, a poor resistance profile or off target pharmacology. We will determine the maximal tolerated dose and basic pharmacodynamic properties (Cmax, AUC, t1/2, oral bioavailability) of the compound class. We will then assess whether our best compounds show effectiveness in a murine S. aureus infection model. In summary, this Phase I project seeks to obtain analogs of our lead compound that have improved potency and selectivity, identify a mechanism of action and to evaluate DMPK properties. We envisage a Phase II project wherein we fully address ADMET issues and greatly expand animal studies with an improved compound set to move our compound class to our eventual goal of an IND filing.
The ability to treat infections has become compromised by growing resistance to current antibiotics and has become a serious threat to public health. The significance of the threat is greater as there have been fewer antibiotics being approved for use in recent years and the discovery of a new class of antibiotic is a rare event. By employing natural product chemistry we have been able to identify a set of novel antibiotics. These compounds are active against a range of pathogens including methicillin-resistant Staphylococcus aureus (MRSA). This project seeks to demonstrate that these compounds can be developed into drugs.
| Hoody, John; Alverson, Jeremy B; Keshipeddy, Santosh et al. (2017) Pharmaceutical analysis of a novel propargyl-linked antifolate antibiotic in the mouse. J Chromatogr B Analyt Technol Biomed Life Sci 1051:54-59 |
