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Mycobacterium tuberculosis modulates its cell surface via an oligopeptide permease (Opp) transport system

Mario Alberto Flores-Valdez^*,1, Rowan P. Morris, Françoise Laval^,, Mamadou Daffé^, and Gary K. Schoolnik^*

^* Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, USA;

Microbiology, Natural Product Unit, Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland;

CNRS, Institut de Pharmacologie et de Biologie Structurale, Département Mécanismes Moléculaires des Infections Mycobactériennes, Toulouse, France; and

Université de Toulouse (Toulouse III), Toulouse, France

¹ Correspondence: Centro de Investigación y Asistencia en Tecnología y diseño del Estado de Jalisco A.C., Normalistas 800, Colinas de la Normal, 44270 Guadalajara, Jalisco, México. E-mail: floresv{at}ciatej.net.mx, floresvz{at}yahoo.com

Bacterial species utilize a vast repertoire of surface structures to interact with their surroundings and employ a number of strategies to reconfigure the cellular envelope according to specific stimuli. Gram-positive bacteria, exemplified by Streptomyces and Bacillus species, control production of some exposed molecules by importing oligopeptide signals via permeases (Opp). Such oligopeptides modulate intracellular signaling pathways. In this work, we functionally characterized an Opp of the human pathogen Mycobacterium tuberculosis (Mtb) and propose its reannotation. Using genome-wide transcriptional profiling, we found that Opp was required to modulate (fold-change ranging from –3.5 to 2.0) the expression of several genes, most of them encoding surface-exposed molecules. These included the virulence-associated lipids mycolic acids and phthiocerol dimycocerosates (PDIMs) as well as PE-family proteins. By thin-layer chromatography and MALDI-TOF-MS we confirmed changes in the lipid profile, including an altered accumulation of triacylglycerides and an affected ratio of mycolic acids to PDIMs. An Opp loss of function mutant showed no in vitro growth defect, but had diminished burden during chronic infection and produced a slightly delayed time to death of animals when compared to WT Mtb infection.—Flores-Valdez, M. A., Morris, R. P., Laval, F., Daffé, M., Schoolnik, G. K. Mycobacterium tuberculosis modulates its cell surface via an oligopeptide permease (Opp) transport system.

Key Words: lipid virulence factors • cell wall modulation • chronic infection • surface interaction