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Browsing by Subject "Antimicrobial Cationic Peptides"
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Item On the in vivo significance of bacterial resistance to antimicrobial peptides(Elsevier, 2015-11) Bauer, Margaret E.; Shafer, William M.; Department of Microbiology & Immunology, IU School of MedicineAntimicrobial peptides (AMPs) are at the front-line of host defense during infection and play critical roles both in reducing the microbial load early during infection and in linking innate to adaptive immunity. However, successful pathogens have developed mechanisms to resist AMPs. Although considerable progress has been made in elucidating AMP-resistance mechanisms of pathogenic bacteria in vitro, less is known regarding the in vivo significance of such resistance. Nevertheless, progress has been made in this area, largely by using murine models and, in two instances, human models of infection. Herein, we review progress on the use of in vivo infection models in AMP research and discuss the AMP resistance mechanisms that have been established by in vivo studies to contribute to microbial infection. We posit that in vivo infection models are essential tools for investigators to understand the significance to pathogenesis of genetic changes that impact levels of bacterial susceptibility to AMPs. This article is part of a Special Issue entitled: Bacterial Resistance to Antimicrobial Peptides.Item Phosphoethanolamine Transferase LptA in Haemophilus ducreyi Modifies Lipid A and Contributes to Human Defensin Resistance In Vitro(PLoS, 2015-04-22) Trombley, Michael P.; Post, Deborah M.B.; Rinker, Sherri D.; Reinders, Lorri M.; Fortney, Kate R.; Zwiki, Beth W.; Janowicz, Diane M.; Baye, Fitsum M.; Katz, Barry P.; Spinola, Stanley M.; Bauer, Margaret E.; Department of Microbiology and Immunology, IU School of MedicineHaemophilus ducreyi resists the cytotoxic effects of human antimicrobial peptides (APs), including α-defensins, β-defensins, and the cathelicidin LL-37. Resistance to LL-37, mediated by the sensitive to antimicrobial peptide (Sap) transporter, is required for H. ducreyi virulence in humans. Cationic APs are attracted to the negatively charged bacterial cell surface. In other gram-negative bacteria, modification of lipopolysaccharide or lipooligosaccharide (LOS) by the addition of positively charged moieties, such as phosphoethanolamine (PEA), confers AP resistance by means of electrostatic repulsion. H. ducreyi LOS has PEA modifications at two sites, and we identified three genes (lptA, ptdA, and ptdB) in H. ducreyi with homology to a family of bacterial PEA transferases. We generated non-polar, unmarked mutants with deletions in one, two, or all three putative PEA transferase genes. The triple mutant was significantly more susceptible to both α- and β-defensins; complementation of all three genes restored parental levels of AP resistance. Deletion of all three PEA transferase genes also resulted in a significant increase in the negativity of the mutant cell surface. Mass spectrometric analysis revealed that LptA was required for PEA modification of lipid A; PtdA and PtdB did not affect PEA modification of LOS. In human inoculation experiments, the triple mutant was as virulent as its parent strain. While this is the first identified mechanism of resistance to α-defensins in H. ducreyi, our in vivo data suggest that resistance to cathelicidin LL-37 may be more important than defensin resistance to H. ducreyi pathogenesis.