Actinomycete-Derived Polyketides as a Source of Antibiotics and Lead Structures for the Development of New Antimicrobial Drugs

Abstract

Actinomycetes are remarkable producers of compounds essential for human and veterinary medicine as well as for agriculture. The genomes of those microorganisms possess several sets of genes (biosynthetic gene cluster (BGC)) encoding pathways for the production of the valuable secondary metabolites. A significant proportion of the identified BGCs in actinomycetes encode pathways for the biosynthesis of polyketide compounds, nonribosomal peptides, or hybrid products resulting from the combination of both polyketide synthases (PKSs) and nonribosomal peptide synthetases (NRPSs). The potency of these molecules, in terms of bioactivity, was recognized in the 1940s, and started the “Golden Age” of antimicrobial drug discovery. Since then, several valuable polyketide drugs, such as erythromycin A, tylosin, monensin A, rifamycin, tetracyclines, amphotericin B, and many others were isolated from actinomycetes. This review covers the most relevant actinomycetes-derived polyketide drugs with antimicrobial activity, including anti-fungal agents. We provide an overview of the source of the compounds, structure of the molecules, the biosynthetic principle, bioactivity and mechanisms of action, and the current stage of development. This review emphasizes the importance of actinomycetes-derived antimicrobial polyketides and should serve as a “lexicon”, not only to scientists from the Natural Products field, but also to clinicians and others interested in this topic.

The antibiotic crisis: How bacterial predators can help

“…However, many BGCs are not yet assigned to their corresponding hypothetical SMs, probably because some of these genes remain silenced (cryptic genes) or are expressed at low levels, yielding low quantities of the respective compounds in the growth conditions assayed [82] , [149] , [160] . The same situation is observed in Streptomyces, a genus notorious for its ability to produce a large quantity and variety of antibiotics and SMs [65] , [161] . Streptomyces genomes are also large and typically contain more than 20 BGCs dedicated to specialized metabolism such as NRPSs and PKSs.…”

<p>Sarecycline: A Review of Preclinical and Clinical Evidence</p>

“…Sarecycline structural modification at C-7 has been attributed to overcoming tetracycline resistance mechanisms and to changing bacterial ribosome binding. 19,26 Possibly because of its unique structural properties and narrow spectrum of antibacterial activity, sarecycline may reduce the emergence of antibiotic-resistant bacterial strains. 19…”

An Update on Molecular Tools for Genetic Engineering of Actinomycetes—The Source of Important Antibiotics and Other Valuable Compounds

“…In the past, transposons (e.g., Tn5) [ 183 , 184 , 185 ], homologous recombination [ 85 , 186 , 187 , 188 , 189 , 190 ] and site-specific recombination based on Cre/ loxP , Dre/ rox [ 101 , 191 ] as well as I-SceI [ 192 , 193 ] systems were extensively used to generate mutants in actinomycetes strains [ 41 , 101 , 194 , 195 , 196 , 197 , 198 , 199 , 200 , 201 ].…”

“…However, many researchers have drawn attention to actinomycetes mainly because of their biosynthetic potential for the production of secondary metabolites [ 41 , 42 , 43 ]. The discovery of the first actinomycete-derived antibiotic (actinomycin) [ 44 ] boosted the isolation of actinomycetes from diverse sources and the traditional screening involving the cultivation, extraction of metabolites and disk diffusion-based activity assays and/or chromatographic analysis [ 43 , 45 , 46 , 47 ].…”