Bioprospecting for Antibacterial Drugs: a Multidisciplinary Perspective on Natural Product Source Material, Bioassay Selection and Avoidable Pitfalls.

Bioprospecting is the exploration, extraction and screening of biological material and sometimes indigenous knowledge to discover and develop new drugs and other products. Most antibiotics in current clinical use (eg. ß-lactams, aminoglycosides, tetracyclines, macrolides) were discovered using this approach, and there are strong arguments to reprioritize bioprospecting over other strategies in the search for new antibacterial drugs. Academic institutions should be well positioned to lead the early stages of these efforts given their many thousands of locations globally and because they are not constrained by the same commercial considerations as industry. University groups can lack the full complement of knowledge and skills needed though (eg. how to tailor screening strategy to biological source material). In this article, we review three key aspects of the bioprospecting literature (source material and in vitro antibacterial and toxicity testing) and present an integrated multidisciplinary perspective on (a) source material selection, (b) legal, taxonomic and other issues related to source material, (c) cultivation methods, (d) bioassay selection, (e) technical standards available, (f) extract/compound dissolution, (g) use of minimum inhibitory concentration and selectivity index values to identify progressible extracts and compounds, and (h) avoidable pitfalls. The review closes with recommendations for future study design and information on subsequent steps in the bioprospecting process.

Alkaloids: an overview of their antibacterial, antibiotic-enhancing and antivirulence activities.

With reports of pandrug-resistant bacteria causing untreatable infections, the need for new antibacterial therapies is more pressing than ever. Alkaloids are a large and structurally diverse group of compounds that have served as scaffolds for important antibacterial drugs such as metronidazole and the quinolones. In this review, we highlight other alkaloids with development potential. Natural, semisynthetic and synthetic alkaloids of all classes are considered, looking first at those with direct antibacterial activity and those with antibiotic-enhancing activity. Potent examples include CJ-13,136, a novel actinomycete-derived quinolone alkaloid with a minimum inhibitory concentration of 0.1 ng/mL against Helicobacter pylori, and squalamine, a polyamine alkaloid from the dogfish shark that renders Gram-negative pathogens 16- to >32-fold more susceptible to ciprofloxacin. Where available, information on toxicity, structure-activity relationships, mechanisms of action and in vivo activity is presented. The effects of alkaloids on virulence gene regulatory systems such as quorum sensing and virulence factors such as sortases, adhesins and secretion systems are also described. The synthetic isoquinoline alkaloid virstatin, for example, inhibits the transcriptional regulator ToxT in Vibrio cholerae, preventing expression of cholera toxin and fimbriae and conferring in vivo protection against intestinal colonisation. The review concludes with implications and limitations of the described research and directions for future research.