Bacterial CETR Projects
Project 1
PI: Thomas Dick, Ph.D.
Primary Institution: HMH-CDI
Novel rifamycins to improve cure rates and shorten treatment of M. abscessus lung disease
Mycobacterium abscessus (Mab) accounts for most pulmonary infections caused by fast-growing non-
tuberculous mycobacteria (NTM). Incidence and prevalence rates are increasing throughout the world. There is currently no reliable cure for Mab pulmonary disease (Mab-PD) despite year-long multidrug treatments that include underperforming, parenteral and poorly tolerated antibiotics. Among the factors driving the refractory nature of Mab-PD is intrinsic resistance of the pathogen to many drug classes including rifamycins. The major goal of this proposal is to optimize rifamycins specifically for the treatment of Mab lung disease.
Project 2
PIs: David Alland, M.D /Joel Freundlich, Ph.D.
Primary Institution: Rutgers University-New Jersey Medical School
Lead Optimization and Preclinical Development of a small molecule inhibitor of M. avium KasA.
Non-tuberculous mycobacteria (NTM) constitute a major threat to global health with over 200,000 annual
cases in the United States alone. Mycobacterium avium complex (MAC) infections are the most common cause of NTM pulmonary disease, producing a five-year all-cause mortality rate of 25%. M. avium (Mav) accounts for the majority of MAC with M. intracellulare (Mae) being the next most common pathogen in this group. MAC is usually treated with three drugs; however, the success rate of even multi-drug therapy is unacceptably low at ~60%. Furthermore, drug resistance can develop during treatment which may reduce cure rates to as low as 5%. Development of NTM-active drugs has lagged similar efforts for Mycobacterium tuberculosis (Mtb), the causative pathogen of tuberculosis (TB); however, important commonalities exist between these species. Both Mtb and MAC share similar liabilities in essential cell wall factors that could be good drug targets. For example, ethambutol (EMB) targets the biosynthesis of arabinogalactan, which is an essential cell wall component for both Mtb and MAC. Here, we outline a proposal to deliver a first-in-class MAC KasA-targeting preclinical drug candidate as well as a backup candidate for effective therapy against MAC.
Project 3
PI: David Perlin, Ph.D.
Primary Institution: HMH-CDI
Commercial Partner: Merck
Advanced development of a potent dual-targeting TriBE class lead candidate to treat highly drug resistant Neisseria gonorrhoeae
Gonorrhea infections present a critical challenge due to the rise of antimicrobial resistance necessitating new treatment approaches. The TriBE inhibitors show promise as a novel solution against drug-resistant strains that fully aligns with recommendations by the World Health Organization for combating this important public health threat. Advancing this candidate class toward investigational new drug status holds potential for addressing the urgent need for effective antimicrobial agents against drug resistant gonorrhoeae infections
Project 4
PI: Terry Roemer, Ph.D.
Primary Organization/ Commercial entity: Prokaryotics
Pre-clinical Safety and Toxicology Studies of a PO-administered b-lactam-tarocin combination agent to treat methicillin susceptible and resistant staphylococci
In 2019, an estimated 1.3 million deaths were attributed to antimicrobial resistance (AMR), with methicillin-resistant Staphylococcus aureus representing the second leading AMR pathogen. Only one class of orally-bioavailable antibiotics (the oxazolidinones – linezolid and tedizolid) exist to treat such infections. This project will develop a first-in-class orally bioavailable combination product comprising the generic antibiotic dicloxacillin and a novel beta-lactam potentiator for step-down and outpatient treatment of Staphylococcal infections.
Project 5
PI: Richard H. Ebright, Ph.D.
Primary Institution: Rutgers University
Therapeutics for drug-resistant bacteria: arylmyxopyronins
Drug-resistant bacterial infections are a major and growing threat. The proposed work is expected to provide new drug candidates effective against a broad spectrum of drug-resistant bacterial pathogens, including both public-health-relevant bacterial pathogens and biodefense-relevant bacterial pathogens.