Weak Alone, Lethal Together: Exploiting Synthetic Lethality to Beat Antibiotic Resistance
- Ray Sullivan
- May 26
- 2 min read
Professor Mohammad R. “Mo” Seyedsayamdost’s Lab at the Department of Chemistry & Molecular Biology, Princeton University, explores a new strategy to combat the growing threat of antibiotic resistance, specifically focusing on the challenging pathogen Pseudomonas aeruginosa. They utilize the concept of chemical synthetic lethality, where two compounds that are individually non-toxic become lethal when combined, to identify potent and selective drug combinations.
The emergence of antibiotic resistance in bacterial pathogens, particularly the ESKAPE group (including P. aeruginosa), poses a significant threat to global health. Traditional single-compound antibiotic treatments are becoming increasingly ineffective.
Mo’s group used a transposon screen in the presence of low-dose antibiotics (ceftazidime - CEF, and piperacillin - PIP) to identify genes that become conditionally essential. These genes represent potential targets for a second compound that would act in synthetic lethal concert with the antibiotic.
The core idea is that while these low-dose antibiotics don't significantly affect the growth of wild-type P. aeruginosa, they can make certain genes necessary for survival. By disrupting these genes with a transposon, the lab could identify mutants sensitive to the low-dose antibiotic, exhibiting a synthetic lethal phenotype.
The transposon screen identified several conditionally essential genes in the presence of low-dose CEF and/or PIP. The pyrimidine biosynthesis pathway, specifically the enzyme PyrD (dihydroorotate dehydrogenase), emerged as a key target. Inhibition of PyrD was shown to be synthetically lethal with low-dose CEF.
High-throughput screening identified two compounds, nordihydroguaiaretic acid (NDGA) and chlorhexidine (CHX), as inhibitors of P. aeruginosa PyrD. Importantly, these compounds exhibited a chemical synthetic lethal phenotype when combined with low-dose CEF, showing minimal individual toxicity at these concentrations.
Biochemical studies revealed that CHX acts as a denaturant of PyrD, potentially by affecting its stability through a hydrophobic patch. On the other hand, NDGA is a competitive inhibitor of PyrD's ubiquinone binding site.
A crucial finding is that combining low-dose CEF with either NDGA or CHX demonstrated targeted activity against P. aeruginosa while showing minimal impact on various beneficial human gut bacteria tested. This specificity is highly desirable in antibiotic therapy to preserve the healthy microbiome.
They propose two potential models to explain the synthetic lethality. One involves the increased essentiality of UMP synthesis (catalyzed by PyrD) in the presence of low-dose CEF, which targets cell wall synthesis. The other suggests that impairing pyrimidine synthesis by inhibiting PyrD might disrupt biofilm formation, making the bacteria more susceptible to CEF penetration.
While promising, further research is needed to explore the clinical applicability of these drug combinations, including pharmacokinetic and safety profiles, particularly for NDGA. The identified hits beyond PyrD also provide avenues for future investigations.
Overton EN, Zhang Y, Ngecu W, Seyedsayamdost MR. Chemical Synthetic Lethality Screens Identify Selective Drug Combinations against Pseudomonas aeruginosa. ACS Chem Biol. 2025 May 16;20(5):1077-1086. doi: 10.1021/acschembio.5c00076. Epub 2025 Apr 21. PMID: 40258132.
コメント