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Prospective Therapeutic Applications of Bacteriocins as Anticancer Agents
Published in Ananda M. Chakrabarty, Arsénio M. Fialho, Microbial Infections and Cancer Therapy, 2019
Lígia F. Coelho, Nuno Bernardes, Arsénio M. Fialho
Some evidence of anticancer activity has been described in assays where HeLa cells were treated with cinnamycin. In 2003, a study reported that this globular lantibiotic specifically targeted the phospholipid phosphatidylethanolamine (PE) in these cells, disturbing their membranes [22]. Nevertheless, the anticancer potential of duramycin, another PE-binding globular lantibiotic, has been more exhaustively investigated. Duramycin is a 19-residue peptide produced by Streptoverticillium cinnamoneus, and it is one of the very few known small peptides to have a defined and stable 3D structure, being resistant to both thermal and proteolytic degradation [63]. Adding to its antimicrobial potential, duramycin is the object of studies related to antitumor therapies as a solo agent or in conjugation with other drugs or drug-release vehicles [24, 64]. In 2016, in a study executed by Broughton et al., two ovarian cancer cell lines and two pancreatic cancer cell lines were assessed for cell viability by flow cytometry after treatment with a series of duramycin concentrations [24]. Increasing levels of necrosis were observed in all four cell lines in a duramycin concentration-dependent manner. At concentrations as low as 5 μmol/L, cell death was induced in these cell lines and at concentrations above 500 μmol/L, duramycin wielded its highest cytotoxic effect, where around 90% of all cells were necrotic. In the same study, duramycin induced calcium ion (Ca2+) release from the cancer cell lines and confocal microscopy showed duramycin-induced morphological changes, all in a concentration-dependent and time-dependent fashion. These results suggest it is possible that duramycin-induced cell death may be a result of a combination of both loss of intracellular components through membrane pores and membrane destabilization [24].
An overview of lantibiotic biosynthetic machinery promiscuity and its impact on antimicrobial discovery
Published in Expert Opinion on Drug Discovery, 2020
Multiple modes of action have been described for lantibiotics, although all interaction are with the bacterial membrane, the specific nature of the interaction varies greatly. For example, the well known lantibiotic nisin has a dual mode of action involving pore formation and specific interaction with the pyrophosphate group of lipid II, inhibiting cell wall synthesis [20]. A recent study also describes a nonspecific physical mechanism where the degree of membrane deformation depends on the degree of crowding and oligomerization of nisin [21]. Lantibiotic Pep5 causes autolysis of target bacteria [22]. Lacticin 481 and nukacin ISK-1 consist of an N-terminal linear peptide and a globular C-terminus. Initially these agents interact with lipid II, potentially via the conserved sequence in ring A of their structures TXS/TXD/EC that has similarity to the lipid II binding motif present in mersacidin. These agents interfere with membrane associated or extracellular components of peptidoglycan synthesis [23]. Globular class II lantibiotics including mersacidin and actagardine inhibit cell wall synthesis leading to reduced growth and induction of lysis [24,25]. Cinnamycin and duramycin bind to membrane aminophospholipid phosphatidylethanolammine, inhibiting phospholipases [26].
Improving the attrition rate of Lanthipeptide discovery for commercial applications
Published in Expert Opinion on Drug Discovery, 2018
Type I lanthipeptides are elongated and cationic peptides that have been suggested to kill gram-positive bacteria through lipid II binding. The conserved rings A and B structure targets the pyrophosphate, peptidoglycan MurNAc, and first isoprene of cell wall precursor lipid II [10,11]. A recent study showed that the pyrophosphate unit of lipid II is the primary site of nisin binding, while the complete MurNAc moiety is required for high-affinity interactions [12]. No protein receptor is involved in this process; thus, it is hard to be overcome by genetic adaptation. Sequential subculturing of S. aureus and S. pneumoniae in subinhibitory concentrations of a type I lanthipeptide mutacin 1140 for 21 days only resulted in threefold increases in the minimum inhibitory concentrations for the two strains [13]. Type II lanthipeptides are the largest family and it can be divided into two previously defined classes, type AII and type B lanthipeptides. Type AII lanthipeptides are cationic peptides with a linear N-terminal region and a globular C-terminal region. The C-terminal region consists of three intertwined rings. Lacticin 481, nukacin ISK-1, bovicin HJ50, salivaricin A, and salivaricin B are members of this class. This class of lanthipeptides has been suggested to target lipid II with the conserved ring A structure and trigger cell wall precursor accumulation [14,15]. Type B lanthipeptides have relatively rigid and globular structures and do not have a net charge at pH 7. It can be divided into mersacidin group and cinnamycin group. Mersacidin group has been suggested to interact with lipid II in part with the side chain of Glu within the intertwined rings C and D [16], while cinnamycin group has been suggested to target phosphatidylethanolamine (PE) and cause hemolysis [17]. Type III lanthipeptides are modified by trifunctional enzyme LanKC which always incorporate labionin structures in mature peptides [18] (Figures 2(d) and 3(c)) and type III lanthipeptides have distinct functions from type I and II lanthipeptides. For instance, SapB produced by Streptomyces coelicolor serves as biological surfactant and aids in aerial hyphae formation [19], while catenulipeptin may also be involved in aerial mycelium formation in its producing strain Catenulispora acidiphila, although more evidence is required to support this function [18]. In addition, labyrinthopeptins have antiviral activity and relieve neuropathic pain in a mouse model [20]. NAI-112, which carries a unique 6-deoxyhexose moiety on its 13th tryptophan residue and shares no amino acid sequence similarity with labyrinthopeptins, also demonstrates pain-relieving activities in both formalin and chronic constriction injury tests in mice [21]. Type IV lanthipeptides are relatively new with distinct bioactivities compared to other types of lanthipeptides. The first type IV lanthipeptides to be purified in any weighable amount in its natural producing organism is streptocollin [22] and it was shown to have no antimicrobial or antiviral activity. Interestingly, 50 μM streptocollin is able to inhibit protein tyrosine phosphatase IB (PTP1B) and potentiates the action of insulin and leptin, thus might be beneficial for treating type II diabetes.