# Development of novel penems for drug-resistant tuberculosis

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $773,080

## Abstract

PROJECT SUMMARY
In its 2015 report, the World Health Organization declared that tuberculosis (TB) killed more humans than
any other infectious agent. While treatment of drug susceptible TB requires combination therapy for at least
six months, treatment of multidrug-resistant TB (DR-TB) requires treatment with multiple toxic, expensive
and less efficacious second/third line drugs for up to 2 years. Even then, only ~50% of DR-TB cases that
receive treatment have successful outcomes. In a recent study, 12% of treated DR-TB cases developed
additional drug resistance during treatment. Therefore, new drugs and innovative regimens that are
effective against drug-resistant TB are urgently needed.
Development of new drugs and regimens is a core mission of our Center for Tuberculosis Research and our
longstanding industry partner, the TB Alliance. Over the past decade, our Pre-clinical Regimen Identification
Program identified 7 novel drug combinations containing 2-3 drugs unapproved for TB treatment that
subsequently advanced to clinical trials. TB Alliance-funded phase 3 trials are underway (n=2) or being
planned (n=1) for 3 regimens, all of which include MDR-TB patients. Yet, there remains a great need for
potent new, oral agents for safer and more universally active regimens without drug-drug interactions.
Clinical proof-of-concept for TB therapy was recently demonstrated for the carbapenem meropenem in
combination with amoxicillin/clavulanate. We have developed a series of chemically distinct synthetic
penems, with superior whole cell potency over existing carbapenems, owing to their being optimized for
inhibition of non-classical L,D-transpeptidases that comprise the predominant transpeptidase activity during
the final step of peptidoglycan synthesis in M. tuberculosis. We determined the crystal structure of one of
our lead penems (T402) bound to a M. tuberculosis L,D-transpeptidase and proposed a unique mechanism
of action. Structural differences were engineered to enhance potency and selectivity against M. tuberculosis
and to minimize spontaneous resistance. This proposal describes a comprehensive, milestone-driven pre-
clinical development plan with the principal objective of delivering a novel penem and novel penem-
containing regimens ready for IND-enabling toxicity studies and further clinical development for treatment of
DR-TB.

## Key facts

- **NIH application ID:** 9839480
- **Project number:** 5R01AI137329-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** ERIC L NUERMBERGER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $773,080
- **Award type:** 5
- **Project period:** 2018-01-03 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9839480

## Citation

> US National Institutes of Health, RePORTER application 9839480, Development of novel penems for drug-resistant tuberculosis (5R01AI137329-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9839480. Licensed CC0.

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