# Role of ribosome modulating proteins in conferring Mycobacterium abscessus antibiotic resistance

> **NIH NIH R01** · WADSWORTH CENTER · 2020 · $500,324

## Abstract

Project Summary:
 Mycobacterium abscessus (Mab) is a rapidly growing NTM causing skin and soft tissue infections
and pulmonary infections in patients with chronic lung damage. It stands apart as one of the most antibiotic
resistant microbial species, making its infections incredibly difficult to treat. A combination of an oral
macrolide and the aminoglycoside, amikacin, comprises the frontline treatment against Mab. Therapy is
prolonged and low cure rates are deplorable. The poor efficacies of these antibiotics result from various
mechanisms of intrinsic resistance induced in Mab upon exposure to drugs as well as the host
environment.
 Recently we showed that MabHflX, a conserved ribosome-associated GTPase, is required for
macrolide-lincosamide resistance (4). The absence of HflX in a DMs_hflX deletion strain results in an
increased population of 70S ribosomes suggesting that HflX is involved in dissociation of ribosomes stalled
in the presence of antibiotics. However, the detailed mechanism of HflX-mediated antibiotic resistance, as
well as the mechanisms by which antibiotic-bound ribosomal subunits are recycled remain unknown. In
another study we demonstrated a role for ARE-ABCF proteins in macrolide/lincosamide resistance. In Aim
1 of this proposal we will use a combination of genetic, biochemical and structural approaches to determine
the mechanisms of HflX and ABCF-mediated macrolide-lincosamide resistance.
 In another independent study, aminoglycoside resistance in zinc-starved M. smegmatis was found
to originate from ribosome hibernation, which involves binding of mycobacterial protein Y (MPY). We
hypothesize that a low-zinc host environment would similarly result in MPY-dependent ribosome
hibernation during Mab infection, and confer resistance to aminoglycosides including amikacin. In Aim 2
of this proposal, we will determine the role of MabMPY in aminoglycoside resistance of which could
potentially explain the observed discord between in vitro efficiency and in vivo efficacy of the current
treatments (Aim 2).
 The extreme innate antibiotic resistance of Mab presents a unique opportunity to study the
convergence of multiple resistance mechanisms in this pathogen. An in-depth understanding of these
various mechanisms is critical in the development of new therapeutic approaches towards treatment of
Mab infections.

## Key facts

- **NIH application ID:** 10094343
- **Project number:** 1R01AI155473-01
- **Recipient organization:** WADSWORTH CENTER
- **Principal Investigator:** Pallavi Ghosh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $500,324
- **Award type:** 1
- **Project period:** 2020-09-21 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10094343

## Citation

> US National Institutes of Health, RePORTER application 10094343, Role of ribosome modulating proteins in conferring Mycobacterium abscessus antibiotic resistance (1R01AI155473-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10094343. Licensed CC0.

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