Gibson, M. I. | bioRxiv Science

bioRxiv2019

Targeting extracellular glycans: Tuning multimeric boronic acids for pathogen-selective killing of Mycobacterium tuberculosis

Innovative chemotherapeutic agents that are active against Mycobacterium tuberculosis (Mtb) are urgently required to control the tuberculosis (TB) epidemic. The Mtb cell envelope has distinct (lipo)polysaccharides and glycolipids that play a critical role in Mtb survival and pathogenesis and disruption of pathways involved in the assembly of the Mtb cell envelope are the primary target of anti-tubercular agents. Here we introduce a previously unexplored approach whereby chemical agents directly target the extracellular glycans within the unique Mtb cell envelope, rather than the intracellular biosynthetic machinery. We designed and synthesised multimeric boronic acids that are selectivity lethal to Mtb and function by targeting these structurally unique and essential Mtb cell envelope glycans. By tuning the number of, and distance between, boronic acid units high selectivity to Mtb, low cytotoxicity against mammalian cells and no observable resistance was achieved. This non-conventional approach may prevent the development of drug-resistance and will act as a platform for the design of improved, pathogen-specific, next generation antibiotics.

biochemistry↗

bioRxiv2018

Artificial selection of microbial communities to enhance degradation of recalcitrant polymers

Recalcitrant polymers are widely distributed in the environment. This includes natural polymers, such as chitin, but synthetic polymers are becoming increasingly abundant, for which biodegradation is uncertain. Distribution of labour in microbial communities commonly evolves in nature, particularly for arduous processes, suggesting a community may be better at degrading recalcitrant compounds than individual microorganisms. Artificial selection of microbial communities with better degradation potential has seduced scientists for over a decade, but the method has not been systematically optimised nor applied to polymer degradation. Using chitin as a case study, we successfully selected for microbial communities with enhanced chitinase activities but found that continuous optimisation of incubation times between selective generations was of utmost importance. The analysis of the community composition over the entire selection process revealed fundamental aspects in microbial ecology: when incubation times between generations were optimal, the system was dominated by Gammaproteobacteria, main bearers of chitinase enzymes and drivers of chitin degradation, before being succeeded by cheating, cross-feeding and grazing organisms.\n\nImportanceArtificial selection is a powerful and atractive technique that can enhance the biodegradation of a recalcitrant polymer and other pollutants by microbial communities. We show, for the first time, that the success of artificially selecting microbial communities requires an optimisation of the incubation times between generations when implementing this method. Hence, communities need to be transferred at the peak of the desired activity in order to avoid community drift and replacement of the efficient biodegrading community by cheaters, cross-feeders and grazers.

microbiology↗