Scientists engineer new drug candidate to fight deadly mycobacterial infection

In a classic example of scientific problem solving, scientists from the Hackensack Meridian Center for Discovery and Innovation (CDI) and colleagues have published a paper introducing a promising new drug candidate they engineered to target a deadly and emerging infection.

The researchers took a hyper-detailed look into the problem of Mycobacterium abscessus, a cousin of tuberculosis (TB) which is a mounting danger among immunocompromised patients and people suffering from certain lung diseases, and chemically re-engineered a widely-used rifamycin antibiotic so that it can effectively treat these neediest patients. 

The new findings are published in the journal Proceedings of the National Academy of Sciences this week. Two of the authors are the wife-and-husband team of Véronique Dartois, Ph.D., and Thomas Dick, Ph.D., of the CDI. 

A critical new drug could result from this discovery, they conclude.

"This is a successful drug discovery program delivering second-generation rifamycins with improved efficacy specifically against mycobacterial infections," write the authors. "The development candidate… will advance to IND (investigational new drug)-enabling studies to support clinical development."

The conundrum: the current series of antibiotics known as rifamycins were developed in the 1960s and have historically proven very effective against TB itself. But the bacteria M. abscessus has proven molecularly resistant against these drugs. Furthermore, the cystic fibrosis patients who are most endangered by M. abscessus infections are subject to drug-to-drug interactions.

Using a "medicinal chemistry rationale," the team of scientists tailored compounds to address all these limitations. Over the course of five years, they designed analogs of rifabutin which would overcome the drug resistance, maintain potent on-target activity, and exhibit favorable oral pharmacokinetics - all while eliminating unwanted interactions with other medications, a liability of rifamycins. 

Two of all the compounds tested through in-vitro an in-vivo models stood out as being especially effective against M. abscessus. But these next-generation rifamycins also have promise in treating other rapid-growing nontuberculous mycobacteria (NTM), as well as against Mycobacterium avium complex (MAC), and TB. M. abscessus remains the primary target. The potentially-deadly infection has been increasing among cystic fibrosis patients at an alarming rate, according to recent research in the journal BMC Infectious Diseases. 

The prevalence and spread of this threat is still being studied. NIH findings have indicated that high levels of some minerals and metals in environmental water supplies may increase the risk of NTM pulmonary infections in people with cystic fibrosis.

Dr. Dick said the work to this goal began almost a decade ago at the Department of Microbiology and Immunology, Yong Loo Lin School of Medicine at the National University of Singapore, specifically citing Dinah Binte Aziz, Jian Liang Low, and Mu-Lu Wu. The early mechanists and drug discovery work was led by Uday Ganapathy, Ph.D., then a member of the Dick Lab at the CDI.

This achievement is the result of a remarkable collaboration between academic investigators, students, and postdoctoral researchers at the CDI, Hackensack Meridian Health, and partner laboratories across the U.S., Europe and Asia."

Thomas Dick, Ph.D., CDI

Key to this work were: Dr. Courtney Aldrich and team, with major contributions from medicinal chemist Tian Lan at the University of Minnesota; and Dr. Mercedes Gonzales-Juarrero and colleagues at Colorado State University.

"The present work constitutes a significant step towards the development of second-generation rifamycins with improved efficacy and pharmacological properties against mycobacterial infections," they conclude.