GSE127838
Polyketide synthase function is a determinant of bacterial persistence and antibiotic tolerance in Burkholderia thailandensis
Persister cells are genetically identical variants in a bacterial population that have phenotypically modified their physiology to survive environmental stress. .  To better define general persistence mechanisms that can be targeted to develop anti-persistence therapeutics, we performed transcriptomics analyses of Burkholderia thailandensis enriched for persisters using three methods: flow sorting by low proton motive force, meropenem treatment, and culture aging. Although the three persister populations generally expressed divergent gene expression profiles that underscores the multi-mechanistic nature of persistence, there were several common gene pathways expressed in two or more persister populations, including polyketide and non-ribosomal peptide synthesis,  Clp proteases, mobile elements, enzymes involved in the lipid metabolism, and ATP-binding cassette (ABC) transporter systems. In particular, identification of genes that encode for polyketide synthases (PKS) and fatty acid catabolism indicate that generation of secondary metabolites, natural products, and complex lipids are needed for the maintenance of the persistence state.  Persisters are markedly reduced in transposon mutants of the PKS gene BTH_I2366. Furthermore, treatment of multiple bacterial pathogens with the fatty acid synthesis inhibitor, CP-640186, potentiated antibiotic efficacy against the persisters. All together, our results suggest that bacterial persisters may exhibit an outward dormant physiology, but maintain active metabolic processes that are required to maintain persistence. Overall design: Comparative analysis of the transcriptome profile of B.thailandensis persister populations isolated from three independent phenotypic screens: low proton motif force, exposure to beta-lactam antibiotic, and 3-week old cultures on solid media