Ability of Innate Defence Regulator Peptides IDR-1002, IDR-HH2 and IDR-1018 to Protect against Mycobacterium tuberculosis Infections in Animal Models

Rivas-Santiago, Bruno; Castañeda-Delgado, Julio Enrique; Santiago, Cesar E. Rivas; Waldbrook, Matt; González-Curiel, Irma; León-Contreras, Juan Carlos; Enciso-Moreno, José Antonio; Villar, Victor del; Mendez-Ramos, Jazmin; Hancock, Robert E. W.; Hernández-Pando, Rogelio

doi:10.1371/journal.pone.0059119

Cited by 107 publications

(78 citation statements)

References 21 publications

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“…Moreover, HDPs can also modulate cytokine production to control the inflammatory response [14,15,19,28,38] and thereby may reduce the risk of developing inflammatory osteolysis. IDR-1018 is one of the most attractive of the HDPs [1,26,30,32,37,39,42]. The purposes of our study were therefore (1) to more fully characterize the immunomodulatory effects of IDR-1018, especially in response to S aureus; and (2) to determine whether IDR-1018 decreases S aureus infection of orthopaedic implants in mice and thereby protects the implants from failure to osseointegrate.…”

Section: Discussionmentioning

confidence: 99%

“…Innate defense regulator peptide-1018 (IDR-1018) is a synthetic 12-amino acid derivative of bactenecin, a bovine HDP [42]. IDR-1018 can directly kill bacteria [42], can modulate differentiation and activation of macrophages and neutrophils, thereby regulating their production of chemokines and cytokines [1,26,30,32,37,42], can reduce soft tissue infections [1,37], and can disrupt bacterial biofilms [25,35]. IDR-1018 was chosen as the focus of this study because it is the most potent IDR that has been described [37] and is therefore an attractive agent to potentially reduce orthopaedic infections and inflammatory osteolysis around orthopaedic implants.…”

Section: Introductionmentioning

confidence: 99%

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Immunomodulatory Peptide IDR-1018 Decreases Implant Infection and Preserves Osseointegration

Choe

Narayanan

Gandhi

et al. 2015

Clinical Orthopaedics &Amp; Related Research

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Background Innate defense regulator peptide-1018 (IDR-1018) is a 12-amino acid, synthetic, immunomodulatory host defense peptide that can reduce soft tissue infections and is less likely to induce bacterial resistance than conventional antibiotics. However, IDRs have not been tested on orthopaedic infections and the immunomodulatory effects of IDR-1018 have only been characterized in response to lipopolysacharide, which is exclusively produced by Gram-negative bacteria. Questions/purposes We sought (1) to more fully characterize the immunomodulatory effects of IDR-1018, especially in response to Staphylococcus aureus; and (2) to determine whether IDR-1018 decreases S aureus infection of orthopaedic implants in mice and thereby protects the implants from failure to osseointegrate. Methods In vitro effects of IDR-1018 on S aureus were assessed by determining minimum inhibitory concentrations in bacterial broth without and with supplementation of physiologic ion levels. In vitro effects of IDR-1018 on macrophages were determined by measuring production of monocyte chemoattractant protein-1 (MCP-1) and proinflammatory cytokines by enzyme-linked immunosorbent assay. In vivo effects of IDR-1018 were determined in a murine model of S aureus implant infection by quantitating bacterial burden, macrophage recruitment, MCP-1, proinflammatory cytokines, and osseointegration in nine mice per group on Day 1 postimplantation and 20 mice per group on Day 15 postimplantation. Results IDR-1018 demonstrated antimicrobial activity by directly killing S aureus even in the presence of physiologic ion levels, increasing recruitment of macrophages to the site of infections by 40% (p = 0.036) and accelerating S aureus clearance in vivo (p = 0.008) with a 2.6-fold decrease in bacterial bioburden on Day 7 postimplantation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Immunomodulatory Peptide IDR-1018 Decreases Implant Infection and Preserves Osseointegration

Choe

Narayanan

Gandhi

et al. 2015

Clinical Orthopaedics &Amp; Related Research

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“…The change in IL-1β-induced proteome is 266 OTVOS evident from the alteration of the expression of NF-κB and JNK pathway members. Two other analogs, IDR-HH2 and IDR-1018, fail to kill M. tuberculosis in vitro to any noticeable degree but reduce bacterium loads in drug-sensitive as well as drug-resistant M. tuberculosis infections [91]. In a mouse model, the leading drug candidate, IDR-1018 (Table I) also reduces lung inflammation as detected by reduced pneumonia.…”

Section: Innate Defense Regulatorsmentioning

confidence: 99%

Immunomodulatory effects of anti-microbial peptides

Ötvös¹

2016

Acta Microbiologica et Immunologica Hungarica

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Anti-microbial peptides (AMPs) were originally thought to exert protecting actions against bacterial infection by disintegrating bacterial membranes. Upon identification of internal bacterial targets, the view changed and moved toward inhibition of prokaryote-specific biochemical processes. However, the level of none of these activities can explain the robust efficacy of some of these peptides in animal models of systemic and cutaneous infections. A rapidly growing panel of reports suggests that AMPs, now called host-defense peptides (HDPs), act through activating the immune system of the host. This includes recruitment and activation of macrophages and mast cells, inducing chemokine production and altering NF-κB signaling processes. As a result, both pro-and anti-inflammatory responses are elevated together with activation of innate and adaptive immunity mechanisms, wound healing, and apoptosis. HDPs sterilize the systemic circulation and local injury sites significantly more efficiently than pure single-endpoint in vitro microbiological or biochemical data would suggest and actively aid recovering from tissue damage after or even without bacterial infections. However, the multiple and, often opposing, immunomodulatory functions of HDPs require exceptional care in therapeutic considerations.

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“…Ultrastructure investigations were adopted from Rivas-Santiago et al, [36,37]. TEM was used to investigate the mechanism of action CMS and would have on the ultrastructure of MTB.…”

Section: Ultrastructure Analysis Of M Tuberculosis Treated With Cmsmentioning

confidence: 99%

The antimicrobial effect of colistin methanesulfonate on Mycobacterium tuberculosis in vitro

Breda¹,

Buys²,

Apostolides³

et al. 2015

Tuberculosis

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Please cite this article in press as: van Breda SV, et al., The antimicrobial effect of colistin methanesulfonate on Mycobacterium tuberculosis in vitro, Tuberculosis (2015), http://dx.doi.org/10.1016/j.tube.2015.05.005 SUMMARYPolymyxins have previously been described to have activity against M. tuberculosis (MTB), but further research was abandoned due to systemic toxicity concerns to achieve the required MIC. Colistin methanesulfonate (CMS), a polymyxin, is well tolerated when inhaled directly into the lungs, resulting in high local concentrations.We report here for the first time, MIC and MBC data for CMS determined by the microtiter Alamar Blue assay (MABA). We also determined how the MIC would be

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Ability of Innate Defence Regulator Peptides IDR-1002, IDR-HH2 and IDR-1018 to Protect against Mycobacterium tuberculosis Infections in Animal Models

Cited by 107 publications

References 21 publications

Immunomodulatory Peptide IDR-1018 Decreases Implant Infection and Preserves Osseointegration

Immunomodulatory Peptide IDR-1018 Decreases Implant Infection and Preserves Osseointegration

Immunomodulatory effects of anti-microbial peptides

The antimicrobial effect of colistin methanesulfonate on Mycobacterium tuberculosis in vitro

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