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Challenges to the Clinical Implementation of Personalized Nutrition
Published in Nilanjana Maulik, Personalized Nutrition as Medical Therapy for High-Risk Diseases, 2020
Diego Accorsi, Nilanjana Maulik
Once all necessary patient variables have been acquired and stored, they must be analyzed. However, part of the definition of big data is a complexity and depth that makes conventional analysis difficult (Ross, Wei et al. 2014). To that end it may be necessary to incorporate less conventional methods, such as artificial intelligence. With these technologies, it becomes possible to analyze large amounts of complex and interacting data with pre-crafted computational parameters and algorithms based on current understanding of underlying genetic, molecular and pathological mechanisms. For example, Leber et al. used one such algorithm to predict outcomes using an ‘in silico’ pipeline, for multiple artificial subjects undergoing alternative treatments for Clostridium difficile (anti-toxin antibodies, fecal transplant, immunomodulators, etc.), using data collected regarding immune response (e.g. T-cell ratios), gut microbiome and time of clearance, while adhering to many known biological and molecular pathways (Leber, Hontecillas et al. 2017). Using this pipeline, the authors managed to establish the therapeutic potential of bis-(benzimidazolyl)-terephthalanilide (BTTs) NSC61610, an immunomodulator involved in the lanthionine synthetase C-like 2 (LANCL2) pathway, in the management of C. difficile colitis, an effect which was then validated through an in vivo mice study.
Cell-Cell Communication in Lactic Acid Bacteria
Published in Marcela Albuquerque Cavalcanti de Albuquerque, Alejandra de Moreno de LeBlanc, Jean Guy LeBlanc, Raquel Bedani, Lactic Acid Bacteria, 2020
Emília Maria França Lima, Beatriz Ximena Valencia Quecán, Luciana Rodrigues da Cunha, Bernadette Dora Gombossy de Melo Franco, Uelinton Manoel Pinto
Nisin is a polypeptide member of the antibiotic family called lantibiotics. Thus, it possesses the amino-acid lanthionine in its composition, as the other bacteriocins of this group, besides having methyl-lanthionine, dehydroalanine (Dha) and dehydrobutyrine (Dhb) residues (Dunny and Leonard 1997, Kleerebezem and Quadri 2001, Williams and Delves-Broughton 2003, Jung et al. 2018). The precursor for nisin consists of two parts: a leader peptide, and a modifiable core peptide. The leader peptide contributes to the interaction between nisin and dedicated enzymes (NisB and NisC), to perform post-translational modification in the molecule. NisB dehydrates serines and threonines, while NisC covalently couples thiol groups of Cys to Dha or Dhb. These modified enzymes form a complex with the ABC transport protein (NisT) which is likely involved in the secretion of the modified pre-nisin molecule. Thus, NisB, NisC and NisT consist in a complex of nisin modification enzymes (Kleerebezem and Quadri 2001, Khusainov et al. 2013). The autoregulation process in Lactococcus lactis is mediated by two component regulatory system: the histidine kinase NisK that acts as a sensor for nisin, and the response regulator NisR (Table 2). Once the signal is transduced by autophosphorylation of NisK and subsequent phospho-transfer to NisR, the transcription of target genes is activated (Kuipers et al. 1998, Hilmi et al. 2006, Jung et al. 2018). A similar mechanism is depicted in Figure 1.
Bacteriocins as Anticancer Peptides: A Biophysical Approach
Published in Ananda M. Chakrabarty, Arsénio M. Fialho, Microbial Infections and Cancer Therapy, 2019
Filipa D. Oliveira, Miguel A.R.B. Castanho, Diana Gaspar
Class I bacteriocins, known as lantibiotics or lanthionine-containing antibiotics, are small and low-weighted peptides, usually less than 5 kDa, and have 19 to 38 amino acid residues [22, 56]. These peptides are heat stable and exhibit post-translation modifications, such as the substitution of d-alanine for l-serine amino acid residues [22, 56]. They also contain polycyclic thioether amino acids, such as lanthionine and β-methyllanthionine, which promote the formation of disulfide bonds between amino acid residues, resulting in internal “rings” that confer lantibiotics their unique structure with specific features [22, 56]. Lantibiotics also contain unsaturated amino acids, namely dehydroalanine and 2-aminoisobutyric acid [22, 56]. This complex structure limits a subdivision of the class of lantibiotics, and there are several different proposed subclassifications [56, 60, 61]. A subclassification is based on peptide charge, structure, and target. Type A lantibiotics, such as nisin and lacticin 3147, are screw shaped, elongated, and flexible and exhibit a positive net charge [22, 56]. Such lantibiotics act on the cell membrane, inducing pore formation and leading to the depolarization of the cytoplasmic membrane [22]. Type B lantibiotics exhibit either a neutral or a negative net charge and a globular shape. These lantibiotics’ action consists in disturbing enzymatic reactions occurring within the target cell, interfering with cell wall synthesis, for example [22]. Mersacidin is representative of type B lantibiotics [61].
An overview of lantibiotic biosynthetic machinery promiscuity and its impact on antimicrobial discovery
Published in Expert Opinion on Drug Discovery, 2020
Studies have shown that the biosynthetic genes involved in the modification of nisin, NisB dehydratase, NisT transporter and cyclase NisC, can be efficiently expressed in other organisms including Lactococcus lactis and Escherichia coli under the control of an inducible promotor. NisB and NisC act via the formation of a catalytically active complex, working in an alternating manner to introduce post-translational modifications into the core section of the pre-nisin. The NisB/NisC complex has been shown to only form in the presence of the pre-nisin substrate. The stoichiometry of the post-translational modification complex has been identified as 2:1:1 (NisB: NisC: pre-nisin) [40]. NisB dehydrates serine and threonine residues in the core peptide. During this process a glutamate is transferred from glutamyl RNAGLU to specific serine/threonine side chains within the core peptide introducing glutamylated intermediates [41]. These serine/threonine residues are then converted to dehydroalanine and dehydrobutyrine. NisC then catalyzes a Michael addition of a C-terminal cysteine residue with the dehydrated amino acids, forming thioether rings resulting in the formation of (methyl) lanthionine rings [42]. Studies have highlighted the ability of this system to modify and transport a broad range of subtrates not just lantibiotics, highlighting the broader potential application of this modification system [43–45].
Current developments in lantibiotic discovery for treating Clostridium difficile infection
Published in Expert Opinion on Drug Discovery, 2019
Lantibiotics are ribosomally synthesized, post-translationally modified peptides containing unusual amino acids including lanthionine, and methyl-lanthionine. Modifications found in lantibiotics often include the formation of dehydroalanine and dehydrobutyrine residues caused by the dehydrations of serine and threonine residues, respectively. Lanthionine is formed when the dehydrated residues are cyclized with cysteines forming thioether bridges. Lantibiotics are subgrouped based on the biosynthetic enzymes involved in their production. Type I lantibiotics are modified by two enzymes, a dehydratase (LanB) and a cyclase (LanC) forming flexible elongated structures and are commonly positively charged and ampipathic. Type II lantibiotics are modified by a single enzyme (LanM) which functions as both a cyclase and dehydratase, these tend to be globular, carrying no net charge. For Type III and IV lantibiotics, dehydration is carried out by a central kinase domain and an N-terminal phosphoSer/phosphoThr lyase domain, however the C-terminal cyclization domain of the synthases between type III and IV differ with three metal binding residues that are conserved in type I, II, and IV lantibiotics being absent from type III [21–24].