Mycobacterium tuberculosis (Mtb) adaptation to hypoxia is considered crucial to its prolonged latent persistence in humans. Mtb lesions are known to contain physiologically heterogeneous microenvironments that bring about differential responses from bacteria. Here we exploit metabolic variability within biofilm cells to identify alternate respiratory polyketide quinones (PkQs) from both Mycobacterium smegmatis (Msmeg) and Mtb. PkQs are specifically expressed in biofilms and other oxygen-deficient niches to maintain cellular bioenergetics. Under such conditions, these metabolites function as mobile electron carriers in the respiratory electron transport chain. In the absence of PkQs, mycobacteria escape from the hypoxic core of biofilms and prefer oxygen-rich conditions. Unlike the ubiquitous isoprenoid pathway for the biosynthesis of respiratory quinones, PkQs are produced by type III polyketide synthases using fatty acyl-CoA precursors. The biosynthetic pathway is conserved in several other bacterial genomes, and our study reveals a redox-balancing chemicocellular process in microbial physiology.
Bibliographical noteFunding Information:
We thank Dr. Archana Singh (CSIR-IGIB, India) for her help with scanning electron microscopy. We thank Dr. Vinay Nandicoori (NII, India) and Dr. Vivek Rao (CSIR-IGIB, India) for providing mycobacterial vectors. We thank Dr. H.V. Thulsiram (CSIR-NCL, India) for his help in devising the experimental setup. We thank Prof. Yossef Av-Gay (University of British Columbia, Vancouver, BC, Canada) and Dr. Kate S. Carroll (Scripps Research Institute, Jupiter, FL) for MSH mutants. The reporter construct for the hspX promoter (phspX) was kindly provided by Dr. Jaya S. Tyagi (AIIMS, India). We acknowledge support provided by Manish Kumar for confocal imaging. We thank Rintu Kutum and Anupam K. Mondal (CSIR-IGIB, India) for help with analyzing and designing figures for the manuscript. A.A. acknowledges CSIR for an SRF fellowship. A.S. is grateful for Wellcome/DBT India Alliance fellowships. We gratefully acknowledge CSIR Grants Gencode BSC0123 and NCL-IGIB BSC0124 (to R.S.G.) and NIH Grant AI-070219 (to C.C.A.). We also acknowledge DBT for institutional support to NII and for NMR facility to ICGEB, New Delhi.