Emerging trends in the discovery of natural product antibacterials

Abstract

This article highlights current trends and advances in exploiting natural sources for the deployment of novel and potent anti-infective countermeasures. The key challenge is to therapeutically target microbial pathogens exhibiting a variety of puzzling and evolutionary complex resistance mechanisms. Special emphasis is given to the strengths, weaknesses, and opportunities in the natural product antimicrobial drug discovery arena, and to emerging applications driven by advances in bioinformatics, chemical biology, and synthetic biology in concert with exploiting the microbial phenotype. These orchestrated efforts have identified a critical mass of lead natural antimicrobials chemical scaffolds and discovery technologies with high probability of successful implementation against emerging microbial pathogens.

Approaches, Challenges and Prospects of Antimalarial Drug Discovery from Plant Sources

“…Other problems with plant-based drug discovery process range from the basic ones like sustainable access to plant material, seasonal and environmental variations and legislative issues concerning plant use, to challenges concerning complex fractionation procedures, small quantity of pure compounds and poor pharmacokinetic/physicochemical properties that negatively affect druggability [67]. With an increasing understanding and use of genomics, it is possible that bioactive molecules can be produced more efficiently using plant-cell cultures and genetically modified microbes [68]. This has already been exploited in the production of artemisinin precursors from genetically modified Saccharomyces cerevisiae and Escherichia coli [69].…”

Strategies for Circumventing Bacterial Resistance Mechanisms

“…This opinion implies that disclosures of potentially transformative natural product antibacterials are evident already (Bologa et al 2013;Kirst 2013). Among the most recently registered antibiotics are daptomycin (1) (CUBICIN ® , a lipopeptide with a membrane-based mechanism) , retapamulin (10) (ALTABAX ® /ALTARGO ® , a pleuromutilin that inhibits the 23S rRNA interaction with the 50S subunit of the ribosome with topical Gram-positive activity) (Novak 2011), and fidaxomicin (2) (DIFICID ® , a macrolide that inhibits the RNA polymerase of Gram-positive bacteria, approved as a narrow-spectrum agent against C. difficile) (Sears et al 2013).…”

Synthetic Biology of Antibiotic Production

“…Clearly, the synthetic biology of antibiotics is not going to replace the traditional approaches, but will evolve in close interaction with the molecular characterization of natural biosynthetic gene clusters and their regulation [29]. Between 2000 and 2008, more than 300 new natural compounds with potential antibiotic activity were reported, including 145 metabolites from 13 structural classes that show promisingly high efficiency (minimum inhibitory concentrations between 0.02 and 10 μg ml −1 ; [30]), the majority being phenolic compounds, quinones, and alkaloids.…”

“…Between 2000 and 2008, more than 300 new natural compounds with potential antibiotic activity were reported, including 145 metabolites from 13 structural classes that show promisingly high efficiency (minimum inhibitory concentrations between 0.02 and 10 μg ml −1 ; [30]), the majority being phenolic compounds, quinones, and alkaloids. These continuing studies of mining for natural products -albeit mostly by small companies rather than major pharmaceutical producers [29] -is complemented by the ongoing discovery of entirely novel antimicrobial mechanisms. Russell et al [31] recently reported the discovery of a superfamily of bacterial phospholipases that act as antibacterial effectors in inter-and intra-species interactions by degrading the major component of bacterial cell membranes, namely phosphatidylethanolamine.…”