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Delving through Quorum Sensing and CRISPRi Strategies for Enhanced Surfactin Production
Published in R.Z. Sayyed, Microbial Surfactants, 2022
Shireen Adeeb Mujtaba Ali, R. Z. Sayyed, M. S. Reddy, Hesham El Enshasy, Bee Hameedal
The most popular biosurfactants are lipopeptides for their reliable performance application and structural stability (Mnif and Ghribi 2015). Lipopeptides are most commonly produced by aerobic microorganisms, however Bacillus licheniformis JF–2 which is an anaerobic bacterium also produced lipopeptides (Javaheri et al. 1985). The members of the genus Bacillus are notable producers of broad-spectrum antimicrobial agents, i.e., cyclic lipopeptides (CLPs) (Borriss 2011, Falardeau et al. 2013). They are amphiphile macromolecules of non-ribosomal origin. Structurally they constitute an amino acid or alkyl/hydroxy fatty acid chain with a peptide component. Their synthesis requires non-ribosomal peptide synthetases (NRPSs), which is a multienzyme complex responsible for selection of amino acid sequence and condensation steps in peptide biosynthesis pathway (Sieber and Marahiel 2005). Its producer strain is known to enjoy a selective advantage because of the NRPSs genes flexibility towards arbitrary evolution and innate rearrangements that leads to production of variant forms (Stein 2005).
New Strategies to Discover Non-Ribosomal Peptides as a Source of Antibiotics Molecules
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Mario Alberto Martínez-Núñez, Zuemy Rodríguez-Escamilla, Víctor López y López
Nonribosomal peptides (NRPs) are secondary metabolites with antibiotics properties. They are synthesized on large nonribosomal peptide synthetase (NRPS) enzyme complexes, which means that their synthesis is independent of ribosomes (Finking and Marahiel, 2004). The NRPSs are modularly organized, with each module consisting of several domains, and at least three domains must be present for the formation of the NRPs: adenylation (A) domain, peptidyl carrier protein (PCP) or thiolation (T) domain, and condensation (C) domain which carry out the synthesis of nonribosomal peptides (Drake et al., 2016). The A-domain is responsible for picking the specific amino acid monomers that are incorporated into final NRPs; there are hundreds of different A-domains with different specificities and they have been classified using the Stachelhaus code, each one incorporating a specific amino acid as a monomer (Mohimani et al., 2014). The biosynthesis of the NRPs can be carried out by three types of NRPSs: type A, a linear NRPS in which each enzymatic domain, and therefore each module, is used once during the biosynthesis of the NRPs; type B, an iterative NRPS that uses all its modules more than once during the biosynthesis of a single NRP; whereas Type C is a non-linear NRPS that deviates from the C-A-T domain rule of module formation with certain domains that work more than once during the biosynthesis of a single NRP (Felnagle et al., 2008). Soil-inhabiting microorganisms, such as Actinomycetes and Bacilli, and eukaryotic filamentous fungi are mostly producers of nonribosomal peptides, but marine microorganisms have also emerged as a source for such peptides (Mootz et al., 2002). The first NRP with antibiotic activity used as a drug was the penicillin extracted from the fungus Penicillium notatum by Alexander Fleming (Bennett and Chung, 2001). Today, P. chrysogenum is the most important organism used in the pharmaceutical industry to produce penicillin at the industrial scale, and despite the alarming increase in the dissemination of pathogens resistant to penicillin, the worldwide demand for this antibiotic is still enormous (Prauße et al., 2016). These secondary metabolites represent promising scaffolds for the development of new drugs (Sieber and Marahiel, 2005) due to the great structural diversity they have, derived from having more than 300 different precursors and are not limited to only 20 proteinogenic amino acids (Von Döhren, 1990); for example, NRPs contain amino acids like ornithine or imino acids (Singh et al., 2012). In addition to the above, the amount of modules used by the NRPSs for the synthesis of the NRP, whether the peptide is cyclized (macrocyclic, branched macrocyclic) or not, and its decoration by various modifying enzymes, including glycosyltransferases, carbamoyltransferases, and oxidases, generates an enormous structural diversity (Losey et al., 2001; Walsh et al., 2001; Etchegaray et al., 2004; Felnagle et al., 2008).
Improvement of lipopeptide production in Bacillus subtilis HNDF2-3 by overexpression of the sfp and comA genes
Published in Preparative Biochemistry & Biotechnology, 2023
Jiawen Wang, Yuan Ping, Wei Liu, Xin He, Chunmei Du
In recent years, with the in-depth study of key enzymes and transcription factors of the lipopeptide synthesis pathway, the high production of microbial lipopeptide using more targeted genetically engineered methods has become a major research topic. The basic synthesis of lipopeptide is as follows: a branched-chain fatty acid is synthesized and activated and then connects with amino acids; the peptide chain continuously extends and finally cyclizes to form lipopeptide (Figure 1). The peptide part of the lipopeptide is synthesized in a ribosome-independent manner by complexes of non-ribosomal peptide synthetase (NRPS) enzymes.[14] NRPSs are composed of multiple multifunctional modules that cooperate with each other, and peptide extension can be performed among the modules to further extend a cycle.[15] A typical NRPS extension module consists of an adenylation (A) domain used for activating specific amino acids, a condensation (C) domain used for forming peptide bonds, and a thiolation (T) domain (i.e., peptidyl carrier protein (PCP) domain) used for delivery.[16] Acyl carrier proteins (ACPs) are key functional domains of fatty acid synthetase (FAS), which is required for the biosynthesis of the fatty acid part of the lipopeptide.[17] In Bacillus subtilis, the type II PPTase encoded by sfp gene can use for posttranslational modification of PCPs and ACPs, converting them from the inactive apo-form to the active holo-form.[18,19] Wang et al.[20] increased the iturin A production of B. amyloliquefacienss by 3.2 times, to 17.0 mg/L by overexpressing the sfp gene and knockout of kinA, bdh, dhbF and rapA. Tan et al.[21] increased the fengycin production of B. subtilis 168 that could not produce lipopeptide to 10.4 mg/L by introducing the sfp gene and replacing the original promoter of the degQ gene with the P43 promoter. Therefore, overexpression of the sfp gene is a feasible method to increase lipopeptide production.