Genome mining reveals high incidence of putative lipopeptide biosynthesis NRPS/PKS clusters containing fatty acyl‐AMP ligase genes in biofilm‐forming cyanobacteria

Abstract

Cyanobacterial lipopeptides have antimicrobial and antifungal bioactivities with potential for use in pharmaceutical research. However, due to their hemolytic activity and cytotoxic effects on human cells, they may pose a health issue if produced in substantial amounts in the environment. In bacteria, lipopeptides can be synthesized via several well-evidenced mechanisms. In one of them, fatty acyl-AMP ligase (FAAL) initiates biosynthesis by activation of a fatty acyl residue. We have performed a bioinformatic survey of the cyanobacterial genomic information available in the public databases for the presence of FAAL-containing non-ribosomal peptide synthetase/polyketide synthetase (NRPS/PKS) biosynthetic clusters, as a genetic basis for lipopeptide biosynthesis. We have identified 79 FAAL genes associated with various NRPS/PKS clusters in 16% of 376 cyanobacterial genomic assemblies available, suggesting that FAAL is frequently incorporated in NRPS/PKS biosynthetases. FAAL was present either as a stand-alone protein or fused either to NRPS or PKS. Such clusters were more frequent in derived phylogenetic lineages with larger genome sizes, which is consistent with the general pattern of NRPS/PKS pathways distribution. The putative lipopeptide clusters were more frequently found in genomes of cyanobacteria that live attached to surfaces and are capable of forming microbial biofilms. While lipopeptides are known in other bacterial groups to play a role in biofilm formation, motility, and colony expansion, their functions in cyanobacterial biofilms need to be tested experimentally. According to our data, benthic and terrestrial cyanobacteria should be the focus of a search for novel candidates for lipopeptide drug synthesis and the monitoring of toxic lipopeptide production.

Global analysis of adenylate-forming enzymes reveals β-lactone biosynthesis pathway in pathogenicNocardia

“…Interestingly, the predicted FAALs outnumbered LACS more than tenfold (3,673 to 322). Since both FAALs and LACSs both accept long-chain fatty acids as substrates, these findings support previous reports that the majority of lipid tails in lipopeptides and other natural products may be incorporated through FAAL-mediated activity rather than CoAactivation (23). β-Lactone formation and CoAactivation of long chain fatty acids and were the least common functions likely catalyzed by ANL enzymes in biosynthetic gene clusters ( Fig.…”

“…4A). The lipstatin cluster encodes NRPS and formyltransferase enzymes that attach an N-formyl leucine to the di-alkyl backbone (23). Notably, NRPS and formyltransferase genes were absent from all candidate clusters in Nocardia (Fig.…”

Genomics-guided discovery and structure identification of cyclic lipopeptides from the Bacillus siamensis JFL15

“…In contrast to conventional antibiotics, CLPs cause lethal effects on pathogenic bacteria by disrupting biological membranes through permeabilization; as a result, pathogenic bacteria experience greater difficulty in developing resistance to CLPs than to traditional antibiotics[2,3]. …”

Shared PKS modules in biosynthesis of synergistic laxaphycins

“…Some cyanobacterial natural products have reached clinical trials and are approved as cancer drugs (Luesch et al, 2001; Deng et al, 2013). Cyclic lipopeptides are common among the cyanobacterial natural products and typically contain a single fatty acid as in laxaphycins (Galica et al, 2017) that confers membrane-disruptive properties (Humisto et al, 2019). Laxaphycin family peptides have been shown to be toxic to or inhibit the growth of multiple organisms and cell lines (Gerwick et al, 1989; Frankmölle et al, 1992b; Bonnard et al, 1997; MacMillan et al, 2002; Bonnard et al, 2007; Maru et al, 2010; Luo et al, 2014; Luo et al, 2015; Dussault et al, 2016; Cai et al, 2018; Bornancin et al, 2019).…”