Screening strategies for discovery of antibacterial natural products

Microbial-derived natural products have been a traditional source of antibiotics and antibiotic leads and continue to be effective sources of antibiotics today. The most important of these discoveries were made about 50 years ago. Chemical modifications of natural products discovered during those years continue to produce new clinical agents but their value is now, unfortunately, fading away owing to the exhaustion of opportunities of chemical modifications. The discovery of new natural antibiotics is directly linked to new screening technologies, particularly technologies that can help to eliminate the rediscovery of known antibiotics. In this article, we have reviewed the screening technologies from recent literature as well as originating from authors laboratories that were used for the screening of natural products. The article covers the entire spectrum of screening strategies, including classical empiric whole-cell assays to more sophisticated antisense based hypersensitive Staphylococcus aureus Fitness Test assays designed to screen all targets simultaneously. These technologies have led to the discovery of a series of natural product antibiotics, which have been summarized, including the discovery of platensimycin, platencin, nocathiacins, philipimycin, cyclothialidine and muryamycins. It is quite clear that natural products provide a tremendous opportunity to discover new antibiotics when combined with new hyper-sensitive whole-cell technologies.