Mechanisms and Significance of Bacterial Resistance to Human Cationic Antimicrobial Peptides

Goytia, Maïra; Kandler, Justin L.; Shafer, William M.

doi:10.1007/978-3-0348-0541-4_9

Cited by 8 publications

(9 citation statements)

References 198 publications

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“…Due to the rapid and non-specific mechanisms of action, the risk of resistance development is generally thought to be low (Zasloff, 2002 ). Nonetheless, resistance to AMPs in bacteria does occur and several mechanisms of resistance have been described, including membrane and cell envelope structure alterations increasing positive charge, upregulation of efflux pumps, and proteolytic degradation of the peptides (Goytia et al, 2013 ; Ernst et al, 2015 ). For instance, resistance against the human cathelicidin LL-37 has been reported to involve degradation of the peptide by bacterial proteolytic enzymes, up-regulation of efflux pumps as well as bacterial-induced down-regulation of LL-37 expression in host cells (Bandurska et al, 2015 ).…”

Section: Antimicrobial Peptidesmentioning

confidence: 99%

“…Under low calcium or magnesium ion concentrations, as in blood plasma, P. aeruginosa activates the pmr (polymyxin resistance) operon, which medicates the addition of N-arabinose to its lipopolysaccharide. This renders the outer surface of the bacterial cell more positively charged, repelling the cationic AMPs (Goytia et al, 2013 ). So, resistance of bacteria against AMPs is possible for several bacterial species, however development of such resistance against novel synthetic AMPs has not often been studied.…”

Section: Antimicrobial Peptidesmentioning

confidence: 99%

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Antimicrobial Peptides in Biomedical Device Manufacturing

et al. 2017

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Over the past decades the use of medical devices, such as catheters, artificial heart valves, prosthetic joints, and other implants, has grown significantly. Despite continuous improvements in device design, surgical procedures, and wound care, biomaterial-associated infections (BAI) are still a major problem in modern medicine. Conventional antibiotic treatment often fails due to the low levels of antibiotic at the site of infection. The presence of biofilms on the biomaterial and/or the multidrug-resistant phenotype of the bacteria further impair the efficacy of antibiotic treatment. Removal of the biomaterial is then the last option to control the infection. Clearly, there is a pressing need for alternative strategies to prevent and treat BAI. Synthetic antimicrobial peptides (AMPs) are considered promising candidates as they are active against a broad spectrum of (antibiotic-resistant) planktonic bacteria and biofilms. Moreover, bacteria are less likely to develop resistance to these rapidly-acting peptides. In this review we highlight the four main strategies, three of which applying AMPs, in biomedical device manufacturing to prevent BAI. The first involves modification of the physicochemical characteristics of the surface of implants. Immobilization of AMPs on surfaces of medical devices with a variety of chemical techniques is essential in the second strategy. The main disadvantage of these two strategies relates to the limited antibacterial effect in the tissue surrounding the implant. This limitation is addressed by the third strategy that releases AMPs from a coating in a controlled fashion. Lastly, AMPs can be integrated in the design and manufacturing of additively manufactured/3D-printed implants, owing to the physicochemical characteristics of the implant material and the versatile manufacturing technologies compatible with antimicrobials incorporation. These novel technologies utilizing AMPs will contribute to development of novel and safe antimicrobial medical devices, reducing complications and associated costs of device infection.

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Section: Antimicrobial Peptidesmentioning

confidence: 99%

Section: Antimicrobial Peptidesmentioning

confidence: 99%

Antimicrobial Peptides in Biomedical Device Manufacturing

et al. 2017

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“…Over the millennia, N. gonorrhoeae has developed multiple mechanisms to resist innate host defenses, including cationic antimicrobial peptides/proteins (CAMPs) produced by phagocytes and epithelial cells (1). Phosphoethanolamine (PEA) decoration of the lipid A possessed by N. gonorrhoeae and N. meningitidis has been shown to contribute to their resistance to CAMPs by a mechanism that likely involves a reduction in ionic interactions of CAMPs with the bacterial surface (1-6), resistance of N. gonorrhoeae to complement-mediated killing by normal human serum (3,4), N. gonorrhoeae fitness during experimental infection in mice and humans (5,7), and the proinflammatory potential of N. gonorrhoeae (7,8).…”

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confidence: 99%

Phase-Variable Expression of lptA Modulates the Resistance of Neisseria gonorrhoeae to Cationic Antimicrobial Peptides

Kandler

Joseph

Balthazar

et al. 2014

Antimicrob Agents Chemother

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d Phosphoethanolamine (PEA) decoration of lipid A produced by Neisseria gonorrhoeae has been linked to bacterial resistance to cationic antimicrobial peptides/proteins (CAMPs) and in vivo fitness during experimental infection. We now report that the lptA gene, which encodes the PEA transferase responsible for this decoration, is in an operon and that high-frequency mutation in a polynucleotide repeat within lptA can influence gonococcal resistance to CAMPs.

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“…Over the millennia, these antimicrobials have exerted selective pressure on bacteria to develop mechanisms to resist their action (79). As was recently reviewed (80), CAMP resistance mechanisms expressed by bacteria can have a significant influence on bacterial survival or fitness during infection.…”

Section: Figmentioning

confidence: 99%

The MisR Response Regulator Is Necessary for Intrinsic Cationic Antimicrobial Peptide and Aminoglycoside Resistance in Neisseria gonorrhoeae

Kandler

Holley

Reimche

et al. 2016

Antimicrob Agents Chemother

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dDuring infection, the sexually transmitted pathogen Neisseria gonorrhoeae (the gonococcus) encounters numerous host-derived antimicrobials, including cationic antimicrobial peptides (CAMPs) produced by epithelial and phagocytic cells. CAMPs have both direct and indirect killing mechanisms and help link the innate and adaptive immune responses during infection. Gonococcal CAMP resistance is likely important for avoidance of host nonoxidative killing systems expressed by polymorphonuclear granulocytes (e.g., neutrophils) and intracellular survival. Previously studied gonococcal CAMP resistance mechanisms include modification of lipid A with phosphoethanolamine by LptA and export of CAMPs by the MtrCDE efflux pump. In the related pathogen Neisseria meningitidis, a two-component regulatory system (2CRS) termed MisR-MisS has been shown to contribute to the capacity of the meningococcus to resist CAMP killing. We report that the gonococcal MisR response regulator but not the MisS sensor kinase is involved in constitutive and inducible CAMP resistance and is also required for intrinsic low-level resistance to aminoglycosides. The 4-to 8-fold increased susceptibility of misR-deficient gonococci to CAMPs and aminoglycosides was independent of phosphoethanolamine decoration of lipid A and the levels of the MtrCDE efflux pump and seemed to correlate with a general increase in membrane permeability. Transcriptional profiling and biochemical studies confirmed that expression of lptA and mtrCDE was not impacted by the loss of MisR. However, several genes encoding proteins involved in membrane integrity and redox control gave evidence of being MisR regulated. We propose that MisR modulates the levels of gonococcal susceptibility to antimicrobials by influencing the expression of genes involved in determining membrane integrity. N eisseria gonorrhoeae is a Gram-negative diplococcus and the causative agent of the sexually transmitted infection termed gonorrhea, which is currently the second most reported infection in the United States (1); an estimated 78 million new cases of gonorrhea occurred worldwide in 2012 (2). In addition to the high worldwide prevalence of gonorrhea, strains with resistance to currently or formerly used antibiotics have emerged, and concern has been voiced that without new effective antimicrobials, some cases of gonorrhea may be difficult to treat in future years (3). In addition to its ability to resist classical antibiotics used in treatment, gonococci have evolved mechanisms to evade the antimicrobial action of host compounds that participate in the innate host defense during infection. For instance, the ability of gonococci to resist the antibiotic-like action of host cationic antimicrobial peptides (CAMPs), such as defensins (4) or larger antimicrobial proteins (e.g., bactericidal permeability-increasing protein [5], cathepsin G [6], and CAP37 [7]), has been implicated in its survival within human polymorphonuclear granulocytes (PMNs) (8, 9).Broadly, there are five known ways in which gonococci res...

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Mechanisms and Significance of Bacterial Resistance to Human Cationic Antimicrobial Peptides

Cited by 8 publications

References 198 publications

Antimicrobial Peptides in Biomedical Device Manufacturing

Antimicrobial Peptides in Biomedical Device Manufacturing

Phase-Variable Expression of lptA Modulates the Resistance of Neisseria gonorrhoeae to Cationic Antimicrobial Peptides

The MisR Response Regulator Is Necessary for Intrinsic Cationic Antimicrobial Peptide and Aminoglycoside Resistance in Neisseria gonorrhoeae

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