Related Experiment Video
Updated: Jul 19, 2026
07:50
Assay Development for High-Throughput Drug Screening Against Mycobacteria
Published on: October 25, 2024
New antifolate inhibitors for Mycobacterium avium.
E W Barrow1, W J Suling, L E Seitz
1Department of Veterinary Pathobiology, 250 McElroy Hall, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, Oklahoma 74078, USA. bill.barrow@okstate.edu
Medicinal Chemistry (Shariqah (United Arab Emirates))
|October 5, 2006
Summary
Researchers developed new antifolates targeting Mycobacterium avium dihydrofolate reductase (DHFR). These compounds show promising selective activity against MAC DHFR, offering potential for new treatments.
Area of Science:
- Medicinal Chemistry
- Antimicrobial Drug Discovery
Background:
- Mycobacterium avium complex (MAC) infections pose a significant therapeutic challenge.
- Dihydrofolate reductase (DHFR) is a validated drug target for treating mycobacterial infections.
- Previous research identified antifolates as potential candidates against MAC DHFR.
Purpose of the Study:
- To synthesize and evaluate novel 2,4-diamino-5-methyl-5-deazapteridines (DMDP) derivatives.
- To enhance solubility and selectivity for MAC DHFR while maintaining low human DHFR activity.
- To identify potent and selective inhibitors against MAC DHFR.
Main Methods:
- Synthesis of novel 6-[2', 5'-dialkoxyphenyl) methyl]-substituted DMDP analogs.
- Antimicrobial susceptibility testing using a colorimetric alamarBlue(R) microdilution broth assay.
- Enzyme inhibition assays with purified recombinant human, MAC, and Mycobacterium tuberculosis (MTB) DHFR to determine IC(50) values and selectivity ratios (SR).
Main Results:
- Synthesized DMDP analogs demonstrated varied minimal inhibitory concentrations (MICs) against MAC strains (0.25 to >16 microg/mL).
- SRI-20920 exhibited potent activity against MAC strains with MICs of 0.25, 0.25, and 8 microg/mL.
- SRI-20730 displayed high selectivity for MAC DHFR over human DHFR, with an SR of 2,337.
- Activity against MTB was generally lower, with MICs ranging from 4 to >64 microg/mL.
Conclusions:
- The novel DMDP derivatives show significant potential as selective antifolates against MAC DHFR.
- The findings support the continued development of this class of compounds for treating MAC infections.
- Further optimization may lead to clinically viable drugs with improved efficacy and safety profiles.
Related Concept Videos
01:15Antifungal Agents
Amphotericin B is a broad-spectrum antifungal agent that exploits structural differences between fungal and mammalian cell membranes. Its amphipathic structure—featuring a hydrophobic polyene-lactone ring and a hydrophilic region containing mycosamine and carboxylic acid groups—enables selective binding to ergosterol, a sterol predominantly found in fungal plasma membranes. This selective interaction underlies the drug’s antifungal activity, although weak binding to cholesterol contributes to...
01:15Anthelminthic Agents
Anthelmintic drugs differ significantly from antiparasitic therapies targeting protozoa, primarily due to differences in parasite biology. Whereas most protozoal treatments act on proliferating cells, anthelmintics are typically directed against mature, nonproliferative helminths. The therapeutic approach considers the helminth's reliance on neuromuscular coordination, glucose metabolism, and microtubular integrity for survival, reproduction, and localization within the host. Most anthelmintics...
01:21Antiprotozoal Agents
Leishmaniasis is a widespread parasitic disease caused by several Leishmania species. It affects millions of people each year and remains a major public health problem in endemic regions. First-line treatment relies on pentavalent antimonials, including meglumine antimoniate and sodium stibogluconate. Even so, how these drugs work has not been fully clear, especially their interaction with parasite-specific biochemical pathways. One key target is trypanothione reductase (TR), an enzyme that...
01:22Antiviral Nucleoside Inhibitors
Antiviral Nucleoside InhibitorsAntiviral nucleoside inhibitors are structural analogs of natural nucleosides that interfere with viral DNA or RNA synthesis. These compounds selectively target viral polymerases due to their resemblance to host nucleosides, thereby disrupting viral genome replication.Mechanism of Acyclovir ActionAcyclovir is a guanosine analog with a three-carbon acyclic side chain. It selectively targets herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2),...
01:28Inhibitors of Bacterial DNA Synthesis
Bacterial pathogens depend on precise and efficient DNA replication to sustain infection. Two type II topoisomerases—DNA gyrase and topoisomerase IV—are critical to this process, as they resolve DNA supercoiling and unlink chromosomes during replication. Fluoroquinolones, synthetic derivatives of quinolones, exploit this mechanism by stabilizing the transient DNA–enzyme cleavage complex, preventing strand religation, and causing lethal double-strand breaks. These antibiotics are selectively...
01:25Inhibitors of Bacterial Protein Synthesis
Aminoglycosides constitute a highly potent class of bactericidal antibiotics that exert their antimicrobial effects by targeting the bacterial ribosome, specifically disrupting protein synthesis. These polycationic molecules consist of amino-modified sugars linked via glycosidic bonds to an aminocyclitol core such as 2-deoxystreptamine or streptamine. Their strong positive charges facilitate tight binding to the negatively charged phosphate backbone of ribosomal RNA (rRNA), primarily at the 16S...