One small surprise has been the rise in usage/rediscovery of
lipopeptides made by NRP synthetase machineries as antibiotics.
Although daptomycin is the poster child of the past decade, ADEPS
show unanticipated mechanisms, not working through membrane
disruption. Even the polymyxins have come back into prominence,
given the multidrug-resistant profiles of Gram-negative pathogens.
There are certainly many more lipopeptide natural products in the
biosphere, and they may be starting points for combination therapies.
New approaches to interrogation of the biosynthetic capacity of the
microbial world for conditional metabolites suggests new scaffolds
will be found, presumably opening up additional rounds of both
chemical and bioengineering optimization of those novel molecular
scaffolds. Different approaches to synthetic library design may also
enrich the hit rates in whole bacterial screens, especially to combat the
permeability barriers and efflux pumps of the ESKAPE pathogens.