Biotechnology of polyketides: new breath of life for the novel antibiotic genetic pathways discovery through metagenomics

Abstract

The discovery of secondary metabolites produced by microorganisms (e.g., penicillin in 1928) and the beginning of their industrial application (1940) opened new doors to what has been the main medication source for the treatment of infectious diseases and tumors. In fact, approximately 80 years after the discovery of the first antibiotic compound, and despite all of the warnings about the failure of the “goose that laid the golden egg,” the potential of this wealth is still inexorable: simply adjust the focus from “micro” to “nano”, that means changing the look from microorganisms to nanograms of DNA. Then, the search for new drugs, driven by genetic engineering combined with metagenomic strategies, shows us a way to bypass the barriers imposed by methodologies limited to isolation and culturing. However, we are far from solving the problem of supplying new molecules that are effective against the plasticity of multi- or pan-drug-resistant pathogens. Although the first advances in genetic engineering date back to 1990, there is still a lack of high-throughput methods to speed up the screening of new genes and design new molecules by recombination of pathways. In addition, it is necessary an increase in the variety of heterologous hosts and improvements throughout the full drug discovery pipeline. Among numerous studies focused on this subject, those on polyketide antibiotics stand out for the large technical-scientific efforts that established novel solutions for the transfer/engineering of major metabolic pathways using transposons and other episomes, overcoming one of the main methodological constraints for the heterologous expression of major pathways. In silico prediction analysis of three-dimensional enzymatic structures and advances in sequencing technologies have expanded access to the metabolic potential of microorganisms.

Screening of polyketide genes from Brazilian Atlantic Forest soil

“…An important tool to enhance the power of the metagenomic method is bioinformatic analysis, which supports the identification of new genes for several medical and industrial molecule pathways (Gomes et al 2013). The protein sequences exhibited identities of up to 90 % with published sequences according to BLAST analysis, and the function protein was confirmed in the Pfam database (Table 1).…”

“…Analogous approaches for screening polyketides in a soil sample from Jaboticabal, State of Sao Paulo, were carried out (Gomes et al 2013). These authors found a PKS module that exhibited homology with myxobacteria PKS type I (36 % identity and a 50 % BLASTp similarity with Chondromyces crocatus CndA protein, its closest neighbour).…”

“…These authors found a PKS module that exhibited homology with myxobacteria PKS type I (36 % identity and a 50 % BLASTp similarity with Chondromyces crocatus CndA protein, its closest neighbour). Gomes et al (2013) suggested that additional studies devoted to the expression and inactivation of these genes are necessary to prove the role of the discovered genes in polyketide biosynthesis. However, their study demonstrated that metagenomic DNA represents a promising source for screening new genes that can be used in combinatorial biosynthesis experiments aimed to the production of new molecules.…”

“…However, a promising tool for understanding microbial communities in different ecosystems is metagenomics. This approach facilitates the study of entire genomes directly from the environmental samples (Handelsman 2004;Daniel 2005;Bonilla-Rosso et al 2008;Angelov et al 2009;Fu et al 2011;Gomes et al 2013). Brazilian Atlantic Forest is considered to be one of the most important biosphere reserves and it exhibits a high biodiversity.…”

Computational Analysis Reveals Industrial Natural Products and Toxins in Charcoal Rot Pathogen, <i>Macrophomina phaseolina</i>

“…FUNGI are prolific producers of low-molecular-weight molecules with various biological activities, such as antibiotic, immunosuppressive, cholesterol-lowering and antitumour activities [1][2][3][4][5] . In addition, fungi produce natural dyes and mycotoxins which are of importance in dye and food industry 6,7 .…”