Adaptation of Mycobacterium tuberculosis to Biofilm Growth Is Genetically Linked to Drug Tolerance

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Abstract
Mycobacterium tuberculosis (Mtb) spontaneously grows at the air-medium interface forming pellicle biofilms, which harbor more drug tolerant persisters than planktonic cultures. The underlying basis for increased persisters in Mtb biofilms is unknown. Using a Tn-seq approach, we show here that multiple genes that are necessary for fitness of Mtb cells within biofilms, but not in planktonic cultures, are also implicated in tolerance of bacilli to a diverse set of stressors and antibiotics. Thus, development of Mtb biofilms appears to be associated with an enrichment of population, in which challenging growth conditions within biofilm architecture select for cells that maintain intrinsic tolerance to exogenous stresses including antibiotic exposure. We further observed that the intrinsic drug tolerance of constituent cells of a biofilm determines the frequency of persisters. These findings together allow us to propose that the selection of elite cells during biofilm development promotes the frequency of persisters. Furthermore, probing the possibility that the population enrichment is an outcome of unique environment within biofilms, we demonstrate biofilm-specific induction in the synthesis of isonitrile lipopeptides (INLP). Mutation analysis indicates that INLP is necessary for the architecture development of Mtb biofilms. In summary, the study offers an insight into persistence of Mtb biofilms under antibiotic exposure, while identifying INLP as a potential biomarker for further investigation of this phenomenon.
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Funding Information
  • HHS | NIH | NIH Office of the Director (AI132422, AI144474)
  • HHS | NIH | NIH Office of the Director (DP2AT009148, 1S10OD020062)

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