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BME219 Healthcare Administration Question: Tuberculosis (TB) continues to be a devastating infectious disease and remerges as a global health emergency due to an alarming rise of antimicrobial resistance to its treatment. Despite of the serious effort that has been applied to develop effective antitubercular chemotherapies, the potential of antimicrobial peptides (AMPs) remains underexploited. A large amount of literature is now accessible on the AMP mechanisms of action against a diversity of pathogens; nevertheless, research on their activity on mycobacteria is still scarce. In particular, there is an urgent need to integrate all available interdisciplinary strategies to eradicate extensively drug-resistant Mycobacterium tuberculosis strains.   In this context, we should not underestimate our endogenous antimicrobial proteins and peptides as ancient players of the human host defense system. We are confident that novel antibiotics based on human AMPs displaying a rapid and multifaceted mechanism, with reduced toxicity, should significantly contribute to reverse the tide of antimycobacterial drug resistance.   In this review, we have provided an up to date perspective of the current research on AMPs to be applied in the fight against TB. A better understanding on the mechanisms of action of human endogenous peptides should ensure the basis for the best guided design of novel antitubercular chemotherapeutics.  Answer: Tuberculosis: Tuberculosis (TB) is caused by disease causing pathogen called Mycobacterium tuberculosis. Tuberculosis generally affects lungs; however, it can also affect other parts of the body. Most common symptoms of TB include chronic cough with blood-containing sputum, fever, night sweats, and weight loss. TB usually spreads through air when active TB patient cough, spit, speak, or sneeze (Venketaraman et al., 2015). Issues With Current Therapy For TB: Duration and complexity of treatment; and adverse events associated with TB treatment leads to nonadherence to treatment. It results in the suboptimal response and emergence of resistance. Increased incidence of multidrug-resistance and drug-resistant TB are the serious problems associated with TB. Prophylactic treatment of latent TB with drugs like isoniazid is associated with nonadherence to the treatment. Efforts to shorten treatment duration with alternative drugs resulted in the severe adverse events (Mandal et al., 2014). Bacterial Unique Structure: Even though antimicrobial peptides (AMPs) have low level of amino acid sequence, these are associated with similar structural scaffolds. Hence, AMPs have potential antimicrobial action. It is difficult for the antimicrobial agents to cross the microbial cell-wall scaffold because it is composed of complex grid of macromolecules like peptidoglycan, arabinogalactan, and mycolic acids (MAgP complex) (Arranz-Trullén et al., 2017). AMPs: AMPs are small, cationic and amphipathic peptides which make part of the innate immune system; hence, considered as host defence peptides (HDPs). Expression of endogenous AMPs is an effective host defence strategy of living organisms. Characteristics of AMPs like multifunctional model of action, natural origin and effectiveness at low concentration made them potential candidates for anti-tubercular treatment (Arranz-Trullén et al., 2017). Mechanism Of Action: AMPs exhibit its action through three different mechanisms like membrane disruption, metabolic inhibitor and immunomodulator. AMPs exhibit its action on the bacterial membranes. AMPs possess positive charge and these positive charges get attracted towards the negative charges of bacterial membrane.  Immune response develops following infection with mycobacterium. AMPs get engaged in the area of infection in the form of granuloma. AMPs disrupt cell was and plasmatic membrane disruption which results in the membrane pore formation. Membrane disruption mainly occur through three different mechanisms like toroidal pore formation, carpet formation and barrel stave formation. It leads to cytoplasmic leakage and death of bacteria. AMPs inhibit ATPase (Arranz-Trullén et al., 2017). AMP also responsible for protein degradation by exhibiting intracellular actions like nucleic acid binding, inhibition of replication, transcription and inhibition of translocation. Thus, AMPs exhibits its antimicrobial activity through functioning as metabolic inhibitors. AMPs also exhibit its action through functioning as immunomodulators. Through immunomodulation, AMPs doesn’t inhibit bacterial growth; however, it alters immune system of host through mechanisms like chemokine induction, histamine release, and angiogenesis modulation (Gutsmann, 2016). Human Derived AMPs: Human derived AMPs are mainly responsible for the immune host defense against mycobacteria. Human AMPs include cathelicidin, defensins, hepcidins, lactoferrin, azurocidin, elastases, antimicrobial RNases, eosinophil peroxidase, cathepsins, granulysin, calgranulin/calprotectin, ubiquitinated peptides and lipocalin2 (Arranz-Trullén et al., 2017). Synthetic AMPs: Synthetic AMPs are considered as the next generation antibiotics and these are useful to combat drug-resistant strains. Most widely used strategy for synthetic AMPs is to engineer stabilized amphipathic α-helix with selected antimicrobial prone amino acids. Synthetic AMP include 1-C134mer, A18G5, A24C1ac, A29C5FA, A38A1guan, CAMP/PL-D, CP26, d-LAK 120, d-LL37, E2 and E6, HHC-10, hLFcin1-11/ hLFcin17-30, Innate defense regulators like (IDR)1002, -HH2, and IDR-1018, LLAP, LLKKK18, MU1140, MIAP, Pin2 variants, RN3(1-45) RN6(1-45) RN7(1-45), SAMPs-Dma and X(LLKK) 2X: II-D, II-Orn, IIDab, and IIDa (Arranz-Trullén et al., 2017). Human AMPs: Name Source Mode of action Activity Cathelicidin (hCAP18/LL-37) (Torres-Juarez et al., 2015; Yu et al., 2013; Rekha et al., 2015)   Neutrophils,  Monocytes,   Epithelial cells,  Mast cells, Macrophages, Dendritic cells, Natural killer cells. Monocytes,  Epithelial cells,  Mast cells,  Macrophages,  Dendritic cells, Natural killer cells, Mycobacterial cell wall lysis,  Immunomodulation,  Pro-inflammatory action,  Autophagy activation,  Chemotaxis,  Neutrophil extracellular traps (NETs) promotion, Bind with Mycobacterium tuberculosis within  the macrophage phagosome. In vitro, In vivo Defensins (Sharma et al., 2000; Sharma et al., 2001; Rivas-Santiago et al., 2011)   Eosinophils, Macrophages, Epithelial cells, Dendritic cells, Neutrophils Mycobacterial cell membrane lysis (HBD), Membrane pore formation (HNPs),  Mycobacterial growth inhibition,  Dendritic and macrophage cells chemotaxis (HBD/HNPs), Inflammation regulation (HBD), zHNP1),  Intracellular DNA target (HNPs). In vitro, In vivo, ex vivo Hepcidin (Gutsmann, 2016; Yamaji, 2004)   Hepatocytes,  Macrophages,  Dendritic cells,  Lung epithelial cells, Lymphocytes. Mycobacterial cell wall lysis,  Inhibition of mycobacterial infection, Iron homeostasis regulation, Pro-inflammatory activity. In vitro, In vivo Lactoferrin (Hwang et al., 2007) Epithelial cells,  Neutrophils,  Polymorphonuclear (PMN) leukocytes Bacterial cell permeation, Iron kidnapping, Anti-inflammatory activity. In vitro, In vivo Azurocidin (Jena et al., 2012) PMN leukocytes,   Neutrophils Mycobacterial cell wall lysis,  Promotion of phagolysosomal fusion In vitro Elastases (Wong and Jacobs, 2013) Neutrophil azurophilic granules, bone marrow cells, Macrophages Bacterial cell membrane lysis,  Serine protease activity, Cell chemotaxis induction,  Immunomodulation, NETs formation,  Macrophage extracellular traps (METs) formation. In vitro, In vivo Antimicrobial RNases (Becknell et al., 2015) Eosinophils (RNase3/ECP), Neutrophils and monocytes,  Epithelial cells and leukocytes Mycobacterial cell agglutination, Mycobacteria cell wall and membrane lysis.   In vitroI, In vivo, Clinical Eosinophil peroxidase (Pulido et al., 2013) Eosinophils Bacterial cell wall lysis. In vitro Cathepsins (Walter et al., 2015) Neutrophils, Monocytes Mediation of apoptosis pathway, Immunomodualtion. In vitro, In vivo Granulysin (Stenger et al., 1998) Lymphocytes Mycobacterial cell lysis. In vitro Calgranulin/calprotectin (Dhiman et al., 2014) Neutrophils, Monocytes,  Keratinocytes,  Leukocytes Phagolysosomal fusion, Pro-inflammatory action. In vitro, In vivo Ubiquitinated peptides (Gutsmann, 2016) Macrophages Mycobacterial cell lysis. In vitro Lipocalin2 ((Gutsmann, 2016)) Neutrophils Mycobacterial growth inhibition, Immunoregulation. In vitro, In vivo   Synthetic AMPs: Name Source Mode of action Activity 1-C134mer (Kapoor et al., 2011) De novo design by oligo N-substituted glycines (peptoid) and alkylation Pore formation In vitro A18G5, A24C1ac, A29C5FA, and A38A1guan (Hoffmann  and Czihal, 2009) Derived from the insect proline-rich peptide Apidaecin. Steps involved are alkylation, tetramethyl guanidinilation, and polyethylene glycol conjugation. Bacterial membrane permeation and inhibition of protein synthesis In vitro CAMP/PL-D (Ramón-García et al., 2013) Short cationic peptides (10 AA) rich in W and R selected from peptide libraries Pore formation. In vitro CP26 (Rivas-Santiago et al., 2013) Derived from cecropin A: mellitin Bacterial cell wall disruption. In vitro d-LAK 120 (Lan et al., 2014) Synthetic α-helical peptides Pore formation and inhibition of protein synthesis. In vitro, Ex vivo d-LL37 (Jiang et al., 2011) Derived from LL-37 Pore formation and immunomodulatory activity. In vitro E2 and E6 (Rivas-Santiago et al., 2013) Derived from bactenecin (bovine cathelicidin) Bac8c (8 AA) Bacterial cell wall disruption. In vitro HHC-10 (Llamas-González et al., 2013) Derived from bactenecin Bacteria membrane lysis. In vitro, In vivo hLFcin1-11/ hLFcin17-30 (Silva et al., 2014) Derived from lactoferricin (All-R and All-K substitutions) Bacterial cell wall and membrane lysis. In vivo Innate defense regulators [innate defense regulator (IDR)1002, -HH2, IDR-1018] (Rivas-Santiago et al., 2013) Derived from macrophage chemotactic protein-1 (MCP-1) Immunomodulatory and anti-inflammatory activity. In vitro, In vivo LLAP (Chingaté et al., 2015) Derived from LL-37 Inhibition of ATPase. In vitro LLKKK18 (Silva et al., 2016) Derived from LL-37 through Hyaluronic acid nanogel conjugation. Pore formation and immunomodulatory activity. In vivo MU1140 (Ghobrial et al., 2010) Derived from Streptococcus mutans lantibiotics Inhibition of cell wall synthesis. In vivo, In vivo MIAP (Santos et al., 2012) Derived from Magainin-I Inhibition of ATPase. In vitro Pin2 variants (Rodríguez et al., 2014) Derived from short helical peptides like pandinin2 Membrane disruption. In vitro RN3(1-45) RN6(1-45) RN7(1-45) (Pulido et al., 2013) Derived from human RNases N-terminus Bacterial cell wall disruption and cell agglutination and intracellular macrophage killing. In vitro, ex-vivo       Synthetic AMPs (SAMPs-Dma) (Sharma et al., 2015) De novo design through Dimethylamination and imidazolation. Cell penetration and DNA binding. In vitro X(LLKK) 2X: II-D, II-Orn, IIDab, and IIDap (Khara et al., 2014). Short stabilized α-helix amphipatic peptides Pore formation. In vitro Conclusion: In recent past, number of AMPs are discovered to combat resistance in TB. These AMPs exhibit its action through direct killing of bacteria and immunomodulation; hence, there is more potential to evade resistance problem. In future, AMPs with low-cost synthesis method should be prepared because its cost of synthesis is more. AMPs are susceptible to proteolytic cleavage after systemic administration; hence, these should be produced using novel drug delivery systems. It is essential to produce sufficient evidence to address the issues related to peptide-based therapy for TB. References: Arranz-Trullén, J., Lu, L., Pulido, D., Bhakta, S. and Boix, E. (2017) Host Antimicrobial Peptides:  The Promise of New Treatment Strategies against Tuberculosis. Frontiers in Immunology, 8, 1499. doi: 10.3389/fimmu.2017.01499. Becknell, B., Eichler, T.E., Beceiro, S., Li, B., Easterling, R.S. and Carpenter, A.R. 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