Cell-Envelope Remodeling as a Determinant of Phenotypic Antibacterial Tolerance in Mycobacterium tuberculosis

Author(s)

Larrouy-Maumus, Gerald ^{[1, 2]} ; Marino, Leonardo B. ^{[3, 1]} ; Madduri, Ashoka V. R. ^{[4, 5]} ; Ragan, T. J. ^[1] ; Hunt, Debbie M. ^[1] ; Bassano, Lucrezia ^[2] ; Gutierrez, Maximiliano G. ^[6] ; Moody, D. Branch ^{[4, 5]} ; Pavan, Fernando R. ^[3] ; de Carvalho, Luiz Pedro S. ^[1]

Affiliation

^[1] Francis Crick Inst, Mill Hill Lab, Mycobacterial Metab & Antibiot Res Lab, London NW7 1AA - England

^[2] Univ London Imperial Coll Sci Technol & Med, MRC Ctr Mol Bacteriol & Infect, Lab Chem Biol TB Pathogenesis, London SW7 2DD - England

^[3] Sao Paulo State Univ UNESP, Sch Pharmaceut Sci, BR-4801902 Araraquara, SP - Brazil

^[4] Harvard Univ, Sch Med, Boston, MA 02115 - USA

^[5] Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA 02115 - USA

^[6] Francis Crick Inst, Mill Hill Lab, Host Pathogen Interact TB Lab, London NW7 1AA - England

• Document type: Journal article
• Source: ACS INFECTIOUS DISEASES; v. 2, n. 5, p. 352-360, MAY 2016.
• Web of Science Citations: 6

Abstract

The mechanisms that lead to phenotypic antibacterial tolerance in bacteria remain poorly understood. We investigate whether changes in NaCl concentration toward physiologically higher values affect antibacterial efficacy against Mycobacterium tuberculosis (Mtb), the causal agent of human tuberculosis. Indeed, multiclass phenotypic antibacterial tolerance is observed during Mtb growth in physiologic saline. This includes changes in sensitivity to ethionamide, ethambutol, D-cycloserine, several aminoglycosides, and quinolones. By employing organism-wide metabolomic and lipidomic approaches combined with phenotypic tests, we identified a time-dependent biphasic adaptive response after exposure of Mtb to physiological levels of NaCl. A first rapid, extensive, and reversible phase was associated with changes in core and amino acid metabolism. In a second phase, Mtb responded with a substantial remodelling of plasma membrane and outer lipid membrane composition. We demonstrate that phenotypic tolerance at physiological concentrations of NaCl is the result of changes in plasma and outer membrane lipid remodeling and not changes in core metabolism. Altogether, these results indicate that physiologic saline-induced antibacterial tolerance is kinetically coupled to cell envelope changes and demonstrate that metabolic changes and growth arrest are not the cause of phenotypic tolerance observed in Mtb exposed to physiologic concentrations of NaCl. Importantly, this work uncovers a role for bacterial cell envelope remodeling in antibacterial tolerance, alongside well-documented allterations in respiration, metabolism, and growth rate. (AU)

• FAPESP's process: 13/14957-5 - Research potential against tuberculosis of a new class of furoxan compounds and nanostructured compounds of the ruthenium(II) and copper (II)
• Grantee: Fernando Rogério Pavan
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 11/21232-1 - Evaluation of the involvement of eIF5A in the secretory pathway in Saccharomyces cerevisiae
• Grantee: Leonardo Biancolino Marino
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)