An intriguing mycobacterial polysaccharide: recycling, replication and beyond

Overview

Project Summary

Mycobacteria are a global priority for which innovative new treatments are urgently needed (WHO 2017). Although most are environmental saprophytes named nontuberculous mycobacteria (NTM), their ability to opportunistically infect humans from water distribution systems and natural resistance to antibiotics, merge into a serious health threat urging innovative research to date the dated and ineffective drugs in use. Mycobacteria produce rare polymethylated methylglucose (MGLP) and methylmannose polysaccharides (MMP), proposed to modulate fatty-acid metabolism and cell envelope integrity. Such seemingly vital roles prompted us to elucidate their biosynthetic pathways and with this project we unveiled the complete pathway for MMP biosynthesis (Mafalda Costa. 2019. PhD Thesis; Ripoll-Rozada et al. 2019. PNAS). This converging multidisciplinary effort also allowed new insights into the biological role and a novel mechanism for polysaccharide recycling and replication at the genetic, functional and structural levels (Maranha et al. unpublished). To answer other long-lasting questions on MMP structure or immune responses, strategies for large-scale purification of MMP are now in place. This project also allowed determining of the three-dimensional structure of an glycoside hydrolase involved in recovery of fast-growing NTM from nitrogen deprivation (Cereija et al. 2019. IUCrJ), identification of the pathway for a novel secondary metabolite (Manso et al. 2019. mBio), characterization of antibiotic susceptibilities of NTM isolated from hospital surfaces (Pereira et al. 2019. BMC Microbiol) and evaluation of the resistance to near-pasteurization temperatures of a species of NTM which, although rarely being a cause of infection, is ubiquitous in water distribution systems and a suitable indicator of contamination (Alarico et al. 2020. Microbiology). Although health authorities still neglect the fact that the prevalence of NTM disease is seriously underestimated in the European Union, only a strong commitment to NTM research will allow proportional responses to this ominous health threat.

Main Goals

Deciphering novel mycobacterial pathways that can grant new drug targets

Project Details