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Oritavancin
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Oritavancin’s mechanism of action is threefold. The first mechanism of action, as for vancomycin, is through the inhibition of the transglycosylation (polymerization) step of cell wall biosynthesis (Zhanel et al., 2012). During the synthesis process, transport of the disaccharide-pentapeptide units across the cell membrane occurs in the form of a complex with a lipid carrier (i.e. lipid II), and the translocation of the complex across the cell membrane provides the substrate for transglycosylase enzymes to incorporate the disaccharide-pentapeptide monomer into nascent peptidoglycan. Vancomycin and other glycopeptides bind to the d-alanyl-d-alanine terminus of the developing peptidoglycan chain, thus sterically hindering transglycosylation. Although the binding site of oritavancin remains the same as for vancomycin in the first mechanism of action, oritavancin’s affinity for the peptidoglycan terminus far exceeds that of vancomycin, especially for VRE and resistant S. aureus (Cooper et al., 1996). The addition of the hydrophobic side chain allows bacterial cell membrane anchoring, which stabilizes the interaction with lipid II (Kim et al., 2009). Another possible explanation for this increased binding affinity is oritavancin’s ability to form a homodimer prior to binding. Each dimer then has the ability to interact with two developing peptidoglycan precursors instead of the single one afforded by a lone molecule. This, in turn, creates an extra binding site to the cytoplasmic membrane (Allen and Nicas, 2003).
Lactic Acid Bacteria Bacteriocins and their Impact on Human Health
Published in Marcela Albuquerque Cavalcanti de Albuquerque, Alejandra de Moreno de LeBlanc, Jean Guy LeBlanc, Raquel Bedani, Lactic Acid Bacteria, 2020
Svetoslav D Todorov, Michael L Chikindas
Mycobacterium tuberculosis, being one of the most robust and antibiotic resistant microorganisms, still remains one of the most serious challenges for modern medicine (Carroll and O’Mahony 2011). Tuberculosis was always related in part to the low quality of life and widespread malnutrition (Carroll and O’Mahony 2011). In the last decades, tuberculosis once again attracted the attention of the medical professionals due to emerging problems with antibiotic resistance (for review see Todorov et al. 2019). Some factors influencing this process are related to the uncontrolled use of antibiotics. Therefore, there is a growing demand for alternative treatments and prophylactic strategies. Based on traditional medicine, LAB have emerged as promising tools in this resurgent crusade against Mycobacterium tuberculosis, including the Multidrug-Resistant and Extensively Drug Resistant Mycobacterium tuberculosis (Carroll and O’Mahony 2011). Bacteriocins were proposed as possible tools in these processes (Carroll and O’Mahony 2011), suggesting a potential mode of action of bacteriocins in control of Mycobacterium spp., such as involving lipid II and the relevance of modifications of lipid II occurring in Mycobacterium spp. (Carroll and O’Mahony 2011). Carroll et al. (2010), studied modifications in primary structure of known bacteriocins in order to generate more effective antimicrobials against Mycobacterium spp. These modified/engineered bacteriocins effectively inhibited Mycobacterium spp., including Mycobacterium tuberculosis H37Ra, Mycobacterium kansasii CIT11/06, Mycobacterium avium subsp. hominissuis CIT05/03 and Mycobacterium avium subsp. paratuberculosis MAP (ATCC19698) (Carroll et al. 2010). According to Carroll et al. (2010), in order to improve the bacteriocin’s efficacy, these modifications need to be related to amino-acids in positions 21 and 22 of nisin A. The creation, molecular characterization and clinical evaluation of nisin T, nisin S and nisin V may be considered as the first step in the production of species or even sub-species specific bio-engineered anti-mycobacterial peptides (Carroll et al. 2010).
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
Nisin is a low-molecular-weight pentacyclic antibacterial peptide produced by Lactococcus lactis (Table 10.1). As a lantibiotic, this ACP has uncommon post-translational amino acids, such as lanthionine, methyllanthionine, and didehydroalanine. Although studies on nisin antibacterial potential have been performed since the 1950s, specifically on the basis of oral health and food preservation, its anticancer potential was not documented until 2012 [67, 68]. The work of Joo et al. demonstrated in vitro and in vivo that nisin A is cytotoxic to head and neck squamous cell carcinoma (HNSCC) [69]. In this work, nisin was added in different concentrations to three human HNSCC cell cultures, increasing the levels of DNA fragmentations and apoptosis on the basis of changes in the calcium influx, all in concentrations ranging from 20 to 80 μg/ml. By blocking CHAC1, a cation transporter regulator, apoptosis effect is suppressed, which suggests that nisin’s effect against HNSCC cells is mediated by these transporters. Accordingly, the same results were observed in vivo. The HNSCC cells were injected into the floor of the mouth in mice, after which nisin was administrated, resulting in a significant reduction in the tumor burden. No adverse effects in mice resulted from nisin administration. Indeed, nisin was already known to be nontoxic toward animals. In 2015, another study from the same team proved that alternative forms of nisin at 95% purity (nisin AP and ZP with point mutations on residue 27) had a superior cytotoxic effect against the same in vitro and in vivo HNSCC models in comparison with a solution of low-content nisin. In fact, in this study, Nisin ZP increased apoptosis levels in vitro in cancer cells and reduced tumorigenesis in vivo and long-term treatment with nisin ZP extended survival. In addition, nisin did not seem to be cytotoxic either to nonmalignant oral keratinocytes or to the mice [26]. Indeed, the World Health Organization, in 1969, and the Food and Drug administration (FDA), in 1988, approved the consumption of nisin by humans, saying itis safe. It interacts with lipid II, a membrane-bound precursor involved in cell-wall biosynthesis, and generates pores in the target bacterial cells but not in their host [2, 69].
An overview of lantibiotic biosynthetic machinery promiscuity and its impact on antimicrobial discovery
Published in Expert Opinion on Drug Discovery, 2020
Lantibiotics predominantly show high levels of activity against gram-positive pathogens but often exhibit poor levels or no activity against gram-negative pathogens. In nisin for example this is due to lipid II, the target molecule nisin interacts with on the bacterial surface being located in the inner membrane of the gram- negative cell and that the outer membrane is impermeable to the lantibiotic. In an effort to create nisin that can inhibit gram negative bacteria, nisin has been fused to several short peptides that can penetrate the outer membrane of gram-negative bacteria and fused as tails to the C-terminus of either full length or truncated versions of nisin. This strategy was employed to enable the lantibiotic to pass through the outer membrane of gram-negative organisms while maintaining the functionality of the lantibiotic at the cytoplasmic membrane. Nisin has been fused to several anti-gram negative peptides including apidaecin 1b, oncocin with results showing when an eight amino acids (PRPPHPRL) tail from apidaecin 1b was attached to nisin, the activity of nisin against Escherichia coli CECT101 was increased more than two times, thus indicating this was a strategy that could increase the therapeutic range of lantibiotics [71].
Inhibition of methicillin-resistant Staphylococcus aureus (MRSA) biofilm by cationic poly (D, L-lactide-co-glycolide) nanoparticles
Published in Biofouling, 2020
Yang Qiu, Yuqi Wu, Boyao Lu, Guanyin Zhu, Tao Gong, Rui Wang, Qiang Peng, Yuqing Li
The assay indicated that the combination of CNPs and vancomycin resulted in a significant antibacterial effect on MRSA planktonic cells and biofilm formation. As the biochemical mechanism of action of vancomycin is based on the high affinity of this antibiotic for the D-alanyl-D-alanine (D-ala-D-ala) residues, an ubiquitous component of the bacterial cell wall precursor Lipid II (McGuinness et al. 2017), and considering that the vancomycin-resistance mechanism of S. aureus is based on its excess of D-ala-D-ala–terminating cell wall chains (Gardete and Tomasz 2014), it can be speculated that the adsorption of CNPs could help to cover these false targets. Moreover, the reduction in vancomycin MIC for MRSA (Figure 7) suggests a potential application with a low dose of this antibiotic, helping to reduce adverse reactions, thus opening the possibility of clinical applications.
Improving the attrition rate of Lanthipeptide discovery for commercial applications
Published in Expert Opinion on Drug Discovery, 2018
Formulation is important to improve the bioavailability and activity of drugs and may be influenced by the particle size, polymorphism, pH, and solubility of the drug. While studies on lanthipeptide formulations are limited, there are some formulations of nisin with improved features. For example, one study has generated an antimicrobial nanofiber wood dressing by electrospinning nisin into poly(ethylene oxide) and poly(d,l-lactide) blend nanofibers. Active nisin continued to diffuse from the dressings for more than 4 days in vitro; in a murine excisional skin infection model induced by S. aureus, after 7 days, the bacterial burden of wounds treated with nisin-containing nanofiber wound dressing decreased more than four logs compared to control group [63]. In a later study [64], nisin incorporated with 2,3-dihydroxybenzoic acid in nanofibers was able to decrease biofilm formation of MRSA by 88% after 24 h of exposure, while nisin incorporated directly into nanofibers only decreased biofilm formation by 3%. One recent study expanded the spectrum of activity of nisin to gram-negative bacteria by nano-engineering [65]. Nisin was attached onto the surface of a C/Au nanocomposite, generating a nanocomposite with high density of positively charge groups provided by the high local density of nisin molecules. The nanocomposites destabilized the outer membrane of gram-negative bacteria, resulting in nisin lipid II complex and pore formation. Once nisin crosses the outer membrane, it has the same mechanism of action as it does in gram-positive bacteria. C/Au/nisin (7 wt%) demonstrated activity against gram-negative bacteria including E. coli and Pseudomonas aeruginosa, with minimal bactericidal concentrations of 1.5 and 2 μM of nisin.