Nonribosomal Peptides from Marine Microbes and Their Antimicrobial and Anticancer Potential

Abstract

Marine environments are largely unexplored and can be a source of new molecules for the treatment of many diseases such as malaria, cancer, tuberculosis, HIV etc. The Marine environment is one of the untapped bioresource of getting pharmacologically active nonribosomal peptides (NRPs). Bioprospecting of marine microbes have achieved many remarkable milestones in pharmaceutics. Till date, more than 50% of drugs which are in clinical use belong to the nonribosomal peptide or mixed polyketide-nonribosomal peptide families of natural products isolated from marine bacteria, cyanobacteria and fungi. In recent years large numbers of nonribosomal have been discovered from marine microbes using multi-disciplinary approaches. The present review covers the NRPs discovered from marine microbes and their pharmacological potential along with role of genomics, proteomics and bioinformatics in discovery and development of nonribosomal peptides drugs.

Keywords: anticancer; antimicrobial; marine natural products; microbe derived-compounds; nonribosomal peptides.

Figure 1

Structures of marketed NRPs.

Figure 2

Tyrocidine biosynthesis in bacteria B. brevis nonribosomal peptide synthetases of tyrocidine synthesis mainly consist, three NRPSs TycA, TycB, and TycC, which contain 10 modules (TycA comprises one module, TycB three, and TycC six modules) each of those responsible for the incorporation of a cognate amino acid into the growing chain with the help of their domains. The Te domain at the last module of TycC catalyzes peptide cyclization and thereby release of the final product (Mootz et al., 2000).

Figure 3

The Gramicidin S biosynthetic machinery the enzymatic assembly consists of two NRPSs (GrsA and GrsB) and their modules, respectively. Each module is responsible for the incorporation of one monomeric amino acid. The thioesterase domain (TE domain) catalyzes the dimerization of two assembled pentapeptides and subsequent cyclization, resulting in gramicidin S (Hoyer et al., 2007).

Figure 4

(A) Organization of modules and their domains in nonribosomal peptide synthetase enzyme. Each module contains their catalytic domains that catalyze activities, substrate activation (A-domain), covalent loading (CP-domain), and peptide bond formation (C-domain). The first modules always lacks a C domain and is used to initiate nonribosomal peptide synthesis, while those harboring a C-domain qualify for elongation and modules with thioesterase domains (TE) usually in the last domain, for termination of peptide product from enzyme through cyclization or hydrolysis (Prieto et al., 2012). (B) Mechanism of nonribosomal peptide (NRP) synthesis Adenylation domain (A) activates amino acid as aminoacyl-AMP and transfer to PCP domain which condenses coming amino acids by forming peptide bonds. Structural modifications mostly operate by epimerization domains which converts L-amino acid to D-amino acid and vice a versa. Peptide chain thus transfers to TE domain by transesterification reaction by PCP. Finally, TE domain catalyzed product release (NRPs) by either hydrolysis or macrocyclization (Condurso and Bruner, 2012).

Figure 5

Structural organization of the thiocoraline NRPSs. L, AMP-ligase; P, peptidyl-carrier protein domain; C, condensation domain; A, adenylation domain; E, epimerization domain; M, N-methyltransferase domain; TE, thioesterase domain.