Novel rifamycins to improve cure rates and shorten treatment of M. abscessus lung disease

Hackensack University Medical Center, Hackensack NJ

Investigators

Abstract

ABSTRACT 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. Rifamycins are oral antibiotics and pillars of TB therapy owing to their exquisite potency against the obligate pathogen M. tuberculosis (Mtb), favorable pharmacokinetics and excellent penetration to the sites of disease, but they do not achieve acceptable efficacy against Mab-PD due to intrinsic bacterial resistance not associated with polymorphisms or mutations in their RNA polymerase target. Rather, we have shown that M. abscessus inactivates rifamycin via ADP-ribosylation. During the previous funding cycle, we have designed and characterized rifabutin analogs that block enzymatic ribosylation while maintaining binding to the target, are as potent against Mab as rifabutin against Mtb, have similarly attractive pharmacokinetic attributes, and most importantly are devoid of CYP3A4 induction, a major liability of clinical rifamycins. We propose to complete the pharmacological, safety and efficacy profiling of the current frontrunners to declare a preclinical development candidate (PDC), then carry out non-GLP IND-enabling studies while establishing an agreement with a commercial partner and securing additional funding to complete the IND filing package (aim 1). Concomitantly, a backup medicinal chemistry program will leverage the tools and assays developed by our group, the Cores and Projects, to further improve potency, metabolism, site-of-disease pharmacokinetics and selectivity index, each contributing to heightened efficacy at tolerated doses (aim 2). To shorten treatment duration in Mab-PD patients who often present with compromised immune defenses, we will build novel regimens around a bactericidal backbone that can rapidly reduce bacterial burden. This backbone combines oral β-lactams and fluoroquinolones with our novel rifamycins, three safe antibiotic classes with a proven records against mycobacterial lung diseases. Through in vitro and in vivo combination studies, we will prioritize regimens with the greatest potential for sterilization according to their collective ability to reach and clear bacterial populations at the site of disease. Our team combines expertise in the medicinal chemistry of rifamycins, anti-mycobacterial drug discovery, microbiology, infectious disease pharmacology, and drug development, augmented by strong interactions with the three scientific cores to achieve the proposed goals. We expect to deliver a first-in-class rifamycin PDC, a non-GLP IND-enabling data package, improved back-up PDCs, and prioritized all-oral rifamycin-based regimens that can improve cure rates and shorten treatment duration.