REVIEW Triggers and cues that activate antibiotic production by actinomycetes Hua Zhu • Stephanie K. Sandiford • Gilles P. van Wezel Received: 7 May 2013 / Accepted: 30 June 2013 / Published online: 2 August 2013 Ó Society for Industrial Microbiology and Biotechnology 2013 Abstract Actinomycetes are a rich source of natural products, and these mycelial bacteria produce the majority of the known antibiotics. The increasing difficulty to find new drugs via high-throughput screening has led to a decline in antibiotic research, while infectious diseases associated with multidrug resistance are spreading rapidly. Here we review new approaches and ideas that are cur- rently being developed to increase our chances of finding novel antimicrobials, with focus on genetic, chemical, and ecological methods to elicit the expression of biosynthetic gene clusters. The genome sequencing revolution identified numerous gene clusters for natural products in actinomy- cetes, associated with a potentially huge reservoir of unknown molecules, and prioritizing them is a major challenge for in silico screening-based approaches. Some antibiotics are likely only expressed under very specific conditions, such as interaction with other microbes, which explains the renewed interest in soil and marine ecology. The identification of new gene clusters, as well as chemical elicitors and culturing conditions that activate their expression, should allow scientists to reinforce their efforts to find the necessary novel antimicrobial drugs. Keywords Silent antibiotic Á Elicitor Á Soil ecology Á Natural product Á Genome mining Á Streptomyces Introduction The discovery of penicillin by Sir Alexander Fleming [42] opened up a completely new era of chemotherapy. The discovery of numerous antibiotics from primarily soil microorganisms and the near eradication of diseases such as tuberculosis led to the concept that infectious diseases may be something of the past [53]. However, the emer- gence of infectious diseases involving multidrug resistant (MDR) bacterial pathogens since the 1980s means that bacterial infections are still a major threat for human health. According to the World Health Organization (WHO), around 440,000 new cases of multidrug-resistant tuberculosis (MDR-TB) are found annually, causing more than 150,000 deaths. Extensively drug-resistant tuberculo- sis (XDR-TB) has now been reported in 64 countries to date [159]. The explosive increase in infections by patho- gens such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecium (VRE) and fluoroquinolone-resistant Pseudomonas aeru- ginosa is estimated to cause approximately 19,000 deaths per year in the US [70], and the most recent occurrence of pan-antibiotic-resistant infections pose the grave threat of completely untreatable infections [8]. Filamentous microorganisms (fungi and bacteria of the order of Actinomycetales) are the major source of sec- ondary metabolites, producing some 90 % of all known antibiotics [15, 100]. Some two-thirds of all antibiotics are produced by actinomycetes, the majority of which by members of the genus Streptomyces. Until now, tens of thousands of natural antimicrobial products have been isolated from microbial sources, and still these likely rep- resent only a tiny portion of the repertoire of bioactive compounds that can potentially be produced [15, 100]. Also, the microbial biodiversity of soil and marine Special issue: Genome Mining for Natural Products Discovery. H. Zhu Á S. K. Sandiford Á G. P. van Wezel (&) Molecular Biotechnology, Institute of Biology, Leiden University, Sylviusweg 72, 2333 BE Leiden, The Netherlands e-mail: g.wezel@biology.leidenuniv.nl 123 J Ind Microbiol Biotechnol (2014) 41:371–386 DOI 10.1007/s10295-013-1309-z Downloaded from https://academic.oup.com/jimb/article/41/2/371/5995299 by Leiden University / LUMC user on 19 May 2021