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Rational Exploration of 2,4-Diaminopyrimidines as DHFR Inhibitors Active against Mycobacterium abscessus and
Matheus Andrade Meirelles1, Vitor M Almeida2, Jaryd R Sullivan3,4,5
1Department of Organic Chemistry, Institute of Chemistry, University of Campinas, UNICAMP, 13083-970-Campinas, SP, Brazil.
Abstract:
Nontuberculous mycobacteria (NTM) are emerging human pathogens linked to severe pulmonary diseases. Current treatments involve the prolonged use of multiple drugs and are often ineffective. Bacterial dihydrofolate reductase (DHFR) is a key enzyme targeted by antibiotics in Gram-negative bacterial infections. However, existing DHFR inhibitors designed for Gram-negative bacteria often fail against mycobacterial DHFRs. Here, we detail the rational design of NTM DHFR inhibitors based on P218, a malarial DHFR inhibitor. We identified compound 8, a 2,4-diaminopyrimidine exhibiting improved pharmacological properties and activity against purified DHFR, and whole cell cultures of two predominant NTM species: Mycobacterium avium and Mycobacterium abscessus. This study underscores the potential of compound 8 as a promising candidate for the in vivo validation of DHFR as an effective treatment against NTM infections.
Insights
Nontuberculous mycobacteria (NTM) infections are difficult to treat. Researchers designed a new dihydrofolate reductase (DHFR) inhibitor, compound 8, showing promise against NTM bacteria.
Area of Science:
- Microbiology
- Medicinal Chemistry
- Drug Discovery
Background:
- Nontuberculous mycobacteria (NTM) are increasingly recognized as significant human pathogens, particularly causing severe pulmonary diseases.
- Current therapeutic strategies for NTM infections rely on prolonged, multi-drug regimens that frequently demonstrate limited efficacy.
- Bacterial dihydrofolate reductase (DHFR) is a validated antibiotic target, but existing inhibitors are ineffective against mycobacterial DHFR.
Purpose of the Study:
- To rationally design novel inhibitors targeting mycobacterial dihydrofolate reductase (DHFR).
- To identify and characterize a new chemical entity with potent activity against NTM species.
- To evaluate the potential of a novel DHFR inhibitor for treating NTM infections.
Main Methods:
- Rational drug design based on a known malarial DHFR inhibitor (P218).
- Synthesis and chemical characterization of novel 2,4-diaminopyrimidine derivatives.
- Biochemical assays to determine activity against purified NTM DHFR enzymes.
- Whole-cell antimicrobial activity testing against *Mycobacterium avium* and *Mycobacterium abscessus*.
Main Results:
- Identification of compound 8, a 2,4-diaminopyrimidine derivative with enhanced properties.
- Compound 8 demonstrated significant inhibitory activity against purified NTM DHFR.
- Compound 8 exhibited potent activity against both *Mycobacterium avium* and *Mycobacterium abscessus* in whole-cell assays.
Conclusions:
- Compound 8 represents a promising novel therapeutic candidate for NTM infections.
- The study validates DHFR as a viable drug target for NTM treatment.
- Further *in vivo* studies are warranted to assess the efficacy of compound 8.
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