Biosynthesis and regulation of secondary metabolites in microorganisms

Abstract

Secondary metabolites are organic compounds with complex chemical structures and diverse physiological functions. Secondary metabolites include antibiotics, pigments, and other bioactive compounds. Many of these compounds have important agricultural and medical applications. Microorganisms, especially actinomycetes and filamentous fungi, are noted as a rich source of bioactive secondary metabolites. Typically, each species produces several antibiotics, with the profile being species-specific. Secondary metabolites are synthesized from their precursors through multistep biosynthetic pathways. In general, the genes governing the biosynthesis of secondary metabolites are clustered together, and an increasing number of gene clusters responsible for the biosynthesis of secondary metabolites have been discovered. The availability of clusters has accelerated functional investigations of biosynthetic pathways of secondary metabolites. A thorough understanding of the enzymatic process is required for metabolic engineering to improve production of secondary metabolites and for combinatorial biosynthesis to generate novel compounds or derivatives. Elucidation of the biosynthetic process requires knowledge from diverse disciplines, including bioinformatics, chemistry, and genetics. Secondary metabolites are generally produced during the stationary phase of growth in microorganisms. The biosynthesis of secondary metabolites is a complex process involving cascade regulations, and these regulatory mechanisms have been investigated extensively at the transcriptional level. However, regulation could also occur at the pre-transcriptional and/or post-transcriptional levels. Pretranscriptional regulation occurs primarily at the chromatin level (epigenetic regulation), while post-transcriptional regulation is achieved via small non-coding RNAs (sRNAs) and protein degradation machinery. Though still in its infancy, some interesting progress has been made in this field [1,2]. As antibiotics are the most important of the secondary metabolites, we will focus on antibiotics hereafter. The alarming rise in emergence and prevalence of antibiotic resistance poses a major threat to human healthcare. It is clear that novel antibiotics are urgently needed to combat this problem. However, the supply of new antibiotics has declined in the last decade [3]. To reverse this trend, several strategies have been devised to find or create new antibiotics, which we describe in detail below.