Chemical synthetic lethality for antimicrobial therapy

A method for treating melioidosis in a subject, comprising:

• administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising trimethoprim at a subinhibitory concentration and a FolE2 enzyme inhibitor;
• wherein the FolE2 enzyme inhibitor is selected from dehydrocostus lactone, parthenolide, or β-lapachone;
• and
• wherein the combination exhibits chemical synthetic lethality against Burkholderia pseudomallei.

A method for identifying antimicrobial drug targets, comprising:

• screening a library of compounds for growth inhibition of a target bacterial pathogen in the presence of a subinhibitory concentration of a known antibiotic;
• identifying compounds that exhibit no growth inhibition individually but cause growth inhibition when combined with the subinhibitory concentration of the known antibiotic;
• determining the molecular target of the identified compounds;
• and
• validating the molecular target as a conditionally essential enzyme that becomes essential in the presence of the subinhibitory concentration of the known antibiotic.