Polyketide Quinones Are Alternate Intermediate Electron Carriers during Mycobacterial Respiration in Oxygen-Deficient Niches

Abstract

Summary 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.

Oxidative Phosphorylation as a Target Space for Tuberculosis: Success, Caution, and Future Directions

“…Whereas ubiquinone (UQ) serves as the predominant quinone in mitochondria and many Gram-negative bacteria, menaquinones (MK) are the predominant lipoquinones of mycobacteria and many other Gram-positive bacteria (84). It has recently been reported that polyketide derived quinones (PkQ) are alternate lipoquinones that are expressed and function as electron carriers in mycobacterial biofilms (85). The biosynthesis of MK requires two separate pathways (Figure 5).…”

Characterization of an Orphan Type III Polyketide Synthase Conserved in Uncultivated “Entotheonella” Sponge Symbionts

“…Originally thought to be limited to plants, diverse type III PKSs from bacteria have been reported over the last two decades . Their biosynthetic products have a multitude of important functions, for example in providing precursors for antibiotics, such as in vancomycin biosynthesis, as alternative electron acceptors in mycobacterial respiration, or in conferring antibiotic resistance . Polyketides are assembled from simple acyl coenzyme A (CoA) building blocks in repeated rounds of decarboxylative Claisen‐like condensations.…”

Stringent Response Factors PPX1 and PPK2 Play an Important Role in Mycobacterium tuberculosis Metabolism, Biofilm Formation, and Sensitivity to Isoniazid In Vivo

“…In addition, we determined the susceptibility of each strain to various antibiotics and other stresses, as well as their ability to develop biofilms, a potentially important property of persistent M. tuberculosis infection (16,17). Finally, in order to investigate the role of the M. tuberculosis stringent response pathway in bacillary persistence during antibiotic treatment of chronic murine M. tuberculosis infection, we evaluated the therapeutic efficacy of an adjuvant DNA vaccine expressing ppx1, ppk2, as well as sigE and rel Mtb , two other members of the positive-feedback cascade regulating M. tuberculosis intracellular poly(P) homeostasis.…”