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Optimization of rifamycins to overcome intrinsic resistance of nontuberculous mycobacteria to improve treatment of NTM lung disease

Award Number: R01AI177342
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/06/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Optimization of rifamycins to overcome intrinsic resistance of nontuberculous mycobacteria to improve treatment of NTM lung disease - ABSTRACT Non-tuberculosis mycobacteria (NTM) are ubiquitous environmental bacteria comprising rapid- and slow- growing (RGM and SGM) opportunistic pathogens and causing tuberculosis (TB)-like lung disease in patients with pre-existing lung conditions or compromised immunity. The most frequently encountered RGM and SGM are Mycobacterium abscessus and the M. avium complex (MAC), respectively. Other clinically important NTM include M. fortuitum and M. chelonae (RGM), and M. kansasii, M. genavense, M. xenopi, and M. simiae (SGM). The often multiyear-long treatment consists of mostly repurposed and underperforming antibiotic combinations. For many NTM diseases, there is no reliable curative regimen and mortality is high Our overarching goal is to optimize rifamycins to overcome intrinsic resistance and improve treatment of NTM lung disease. Rifampicin (RIF) is the pillar of TB therapy owing to its exquisite potency against the obligate pathogen M. tuberculosis (Mtb), favorable pharmacokinetics and excellent penetration to the sites of disease. Although RIF is recommended for the treatment of all SGM pulmonary diseases but M. simiae, its therapeutic utility has not been established except for M. kansasii disease, in line with RIF being similarly potent against M. kansasii and Mtb but poorly active against all other NTMs. Rifamycins do not achieve acceptable efficacy against most NTM diseases due to intrinsic bacterial resistance not associated with polymorphisms or mutations in their target, the RpoB subunit of the RNA polymerase. Rather, we have shown that M. abscessus undergoes intrabacterial metabolism by rifamycin monooxygenase(s) (ROX) and ADP-ribosylase (Arr). Through systematic genomics searches, we have identified these metabolic enzymes in all major RGM and several SGM. M. kansassii, in line with its favorable response to rifampicin treatment, is Arr-negative. Rifamycin glycosylases and phosphorylases, discovered in other bacteria, are potential additional candidates contributing to intrinsic resistance in some NTM. We propose to characterize the species-specific rifamycin resistome of NTMs and exploit this knowledge to overcome intrinsic resistance and rationally optimize the rifamycin class to improve the treatment of NTM lung disease. Using ROX-resistant rifabutin (RBT) as chemical starting point in preliminary studies, we have blocked ADP-ribosylation, resulting in a dramatic potency improvement against M. abscessus, similar to that of RIF against Mtb (which does not harbor ROX or Arr). We will expand this approach to appropriate RGM and SGM species as guided by resistome findings. To deliver a preclinical development candidate for the treatment of M. abscessus and other Arr-positive NTM lung diseases, medicinal chemistry efforts will focus on reducing plasma protein binding and removing drug-drug interactions due to cytochrome P450 induction, while maintaining potency and favorable penetration into lung lesions. Through combination studies in vitro and in mouse models, we will identify best partner drugs to deliver all-oral bactericidal rifamycin-based combinations that can improve cure rates and shorten treatment duration.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $838,280 )
2025	2025	HMH HOSPITALS CORPORATION	343 THORNALL ST	EDISON	NJ	08837	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	3	5/28/2025	NON-COMPETING CONTINUATION	$838,280
														Subtotal = $838,280

Issue Date FY: 2024 ( Subtotal = $838,280 )
2024	2024	HMH HOSPITALS CORPORATION	343 THORNALL ST	EDISON	NJ	08837	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	2	5/20/2024	NON-COMPETING CONTINUATION	$838,280
														Subtotal = $838,280

Issue Date FY: 2023 ( Subtotal = $857,555 )
2023	2023	HMH HOSPITALS CORPORATION	343 THORNALL ST	EDISON	NJ	08837	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	1	6/6/2023	NEW	$857,555
														Subtotal = $857,555

Grand Total All Awards = $2,534,115

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Optimization of rifamycins to overcome intrinsic resistance of nontuberculous mycobacteria to improve treatment of NTM lung disease

Award Number: R01AI177342

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/06/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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