The PDIM paradox of : new solutions to a persistent problem.

Phthiocerol dimycocerosate (PDIM) is an essential virulence lipid of . culturing rapidly selects for spontaneous mutations that cause PDIM loss leading to virulence attenuation and increased cell wall permeability. We discovered that PDIM loss is due to a metabolic deficiency of methylmalonyl-CoA that impedes the growth of PDIM-producing bacilli. This can be remedied by supplementation with odd-chain fatty acids, cholesterol, or vitamin B. We developed a much-needed facile and scalable routine assay for PDIM production and show that propionate supplementation enhances the growth of PDIM-producing bacilli and selects against PDIM-negative mutants, analogous to conditions. Our results solve a major issue in tuberculosis research and exemplify how discrepancies between the host and nutrient environments can attenuate bacterial pathogenicity.