Platensimycin is a selective FabF inhibitor with potent antibiotic properties

Bacterial infection remains a serious threat to human lives because of emerging resistance to existing antibiotics. Although the scientific community has avidly pursued the discovery of new antibiotics that interact with new targets, these efforts have met with limited success since the early 1960s. Here we report the discovery of platensimycin, a previously unknown class of antibiotics produced by Streptomyces platensis. Platensimycin demonstrates strong, broad-spectrum Gram-positive antibacterial activity by selectively inhibiting cellular lipid biosynthesis. We show that this anti-bacterial effect is exerted through the selective targeting of beta-ketoacyl-(acyl-carrier-protein (ACP)) synthase I/II (FabF/B) in the synthetic pathway of fatty acids. Direct binding assays show that platensimycin interacts specifically with the acyl-enzyme intermediate of the target protein, and X-ray crystallographic studies reveal that a specific conformational change that occurs on acylation must take place before the inhibitor can bind. Treatment with platensimycin eradicates Staphylococcus aureus infection in mice. Because of its unique mode of action, platensimycin shows no cross-resistance to other key antibiotic-resistant strains tested, including methicillin-resistant S. aureus, vancomycin-intermediate S. aureus and vancomycin-resistant enterococci. Platensimycin is the most potent inhibitor reported for the FabF/B condensing enzymes, and is the only inhibitor of these targets that shows broad-spectrum activity, in vivo efficacy and no observed toxicity.     

Seasonal oscillations in water exchange between aquifers and the coastal ocean

Ground water of both terrestrial and marine origin flows into coastal surface waters as submarine groundwater discharge, and constitutes an important source of nutrients, contaminants and trace elements to the coastal ocean. Large saline discharges have been observed by direct measurements and inferred from geochemical tracers, but sufficient seawater inflow has not been observed to balance this outflow. Geochemical tracers also suggest a time lag between changes in submarine groundwater discharge rates and the seasonal oscillations of inland recharge that drive groundwater flow towards the coast. Here we use measurements of hydraulic gradients and offshore fluxes taken at Waquoit Bay, Massachusetts, together with a modelling study of a generalized coastal groundwater system to show that a shift in the freshwater-saltwater interface-controlled by seasonal changes in water table elevation-can explain large saline discharges that lag inland recharge cycles. We find that sea water is drawn into aquifers as the freshwater-saltwater interface moves landward during winter, and discharges back into coastal waters as the interface moves seaward in summer. Our results demonstrate the connection between the seasonal hydrologic cycle inland and the saline groundwater system in coastal aquifers, and suggest a potentially important seasonality in the chemical loading of coastal waters.