Developing new antibacterials through natural product research

Natural products have long been instrumental for discovering antibiotics, but many pharmaceutical companies abandoned this field and new antibiotics declined. In contrast, microbial resistance to current antibiotics has approached critical levels.

This article gives historical perspectives by providing background about present-day economic realities and medical needs for antibiotic research, whose pipeline is mostly focused toward older known agents and newer semi-synthetic derivatives. Future research trends and projected technological developments open many innovative opportunities to discover novel antibacterials and find ways to control pathogenic bacteria without conventional antibiotics that provoke resistance.

The successful registration of daptomycin, retapamulin and fidaxomicin indicate the re-emergence of natural products has already begun. Semi-synthetic derivatives from other under-explored classes are progressing. More effort is being put into approaches such as total synthesis, discovery of new structural scaffolds for synthesis, alterations of biosynthetic pathways, combinatorial biosynthesis, new screening targets and new resources from which to isolate natural products. A return to successful screening of actinomycetes depends on solving the rate-limiting dereplication obstacle. Long-term solutions need to come from greater exploration of the massive numbers of uncultured microbes. An ultimate solution to the antibiotic-promoted microbial resistance cycle may lie in finding ways to control bacteria by non-lethal means.