Increased resistance to cationic antimicrobial peptide LL-37 in methicillin-resistant strains of Staphylococcus aureus

Ouhara, Kazuhisa; Komatsuzawa, Hitoshi; Kawai, Toshihisa; Nishi, Hiromi; Fujiwara, Takanori; Fujiue, Yoshihiro; Kuwabara, Masao; Sayama, Koji; Hashimoto, Koji; Sugai, Motoyuki

doi:10.1093/jac/dkn106

Cited by 69 publications

(56 citation statements)

References 10 publications

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“…MRSA possesses a large repertoire of established ROS and AMP resistance mechanisms (49,60,61), and this may provide functional redundancy that allows greater compensation for loss of bNOS expression. The regulatory effects of endogenous NO are also likely to differ among species, just as differential adaptive responses of S. aureus and B. anthracis to exogenous NO have been described (22,62).…”

Section: Discussionmentioning

confidence: 99%

Methicillin-resistant Staphylococcus aureus Bacterial Nitric-oxide Synthase Affects Antibiotic Sensitivity and Skin Abscess Development

Sorge¹,

Beasley²,

Gusarov

et al. 2013

Journal of Biological Chemistry

117

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Background: Methicillin-resistant Staphylococcus aureus (MRSA) generates NO through bacterial NO synthase (bNOS). Results: Loss of bNOS increases MRSA sensitivity to host neutrophils, cathelicidin antimicrobial peptides, and cell envelopeactive antibiotics. Conclusion: bNOS influences MRSA disease pathology. Significance: Future development of bNOS-specific inhibitors could provide dual activities to reduce MRSA pathology and increase antibiotic effectiveness.

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Section: Discussionmentioning

confidence: 99%

Methicillin-resistant Staphylococcus aureus Bacterial Nitric-oxide Synthase Affects Antibiotic Sensitivity and Skin Abscess Development

Sorge¹,

Beasley²,

Gusarov

et al. 2013

Journal of Biological Chemistry

117

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“…The minimum inhibitory concentration (MIC) of MelitAP-27, antibiotics, and the peptide-antibiotic combinations against the bacterial strains mentioned previously was determined by adapting the microbroth dilution method outlined by the Clinical and Laboratory Standards Institute (CLSI) guidelines (Komatsuzawa et al 2000;Ouhara et al 2008). Briefly, bacterial cells were grown over night in Muller Hinton Broth and diluted to 10 6 CFU/ml in the same medium prior to use.…”

Section: Bacterial Susceptibility Assaymentioning

confidence: 99%

In Vitro Synergistic Activities of the Hybrid Antimicrobial Peptide MelitAP-27 in Combination with Conventional Antibiotics Against Planktonic and Biofilm Forming Bacteria

Almaaytah

Alnaamneh

Abualhaijaa

et al. 2016

Int J Pept Res Ther

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The extensive use of antibiotics for the treatment of human infections during the last few decades has led to a dramatic increase in the emergence of multidrug-resistant bacteria (MDRB) among various bacterial strains. Global research is currently focused on finding novel alternative agents with different mechanisms of action rather than the use of conventional antibiotics to counteract the threat of bacterial and biofilm infections. Antimicrobial peptides represent promising alternative agents for conventional antibiotics as these molecules display a broad spectrum of activity against several microorganisms. Recently, we have designed a novel hybrid antimicrobial peptide named MelitAP-27. This peptide has been found to display potent broad spectrum and selective in vitro antimicrobial activities against a wide range of Gram-positive and Gramnegative bacteria. In the present study, the in vitro antimicrobial and antibiofilm activities of the peptide alone and in combination with five different types of antibiotics were assessed against wild-type and resistant Gram-positive and Gram-negative bacterial strains. Our results showed that most of the combination groups displayed a synergistic mode of action against planktonic and biofilm forming bacteria which resulted in decreasing the effective MIC values for MelitAP-27 to the nanomolar concentrations. These effective concentrations were associated with negligible toxicities on mammalian cells. The results of our study indicate that combinations of MelitAP-27 with conventional antibiotics may be pursued as a potential novel treatment strategy against MDRB and biofilm forming bacteria.

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“…Previous studies had indicated potent activity of LL-37 against most strains of S. aureus (27,28), with MICs in the lower micromolar range and comparable only to the MICs for E. coli. However, a recent study of clinical isolates of S. aureus has found a broad range of susceptibilities to LL-37 in both MSSA and MRSA strains (21). One of the factors contributing to the resistance of some strains of S. aureus to LL-37 is the presence of proteolytic enzymes (25).…”

Section: Micsmentioning

confidence: 99%

Lipid Segregation Explains Selective Toxicity of a Series of Fragments Derived from the Human Cathelicidin LL-37

Epand

Wang²,

Berno

et al. 2009

Antimicrob Agents Chemother

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The only human cathelicidin, the 37-residue peptide LL-37, exhibits antimicrobial activity against both gram-positive and gram-negative bacteria. We studied the ability of several fragments of LL-37, exhibiting different antimicrobial activities, to interact with membranes whose compositions mimic the cytoplasmic membranes of gram-positive or of gram-negative bacteria. These fragments are as follows: KR-12, the smallest active segment of LL-37, with the sequence KRIVQRIKDFLR, which exhibits antimicrobial activity only against gram-negative bacteria; a slightly smaller peptide, RI-10, missing the two cationic residues at the N and C termini of KR-12, which has been shown not to have any antimicrobial activity; a longer peptide, GF-17, which shows antimicrobial activity against gram-positive as well as gram-negative bacteria; and GF-17D3, with 3 D-amino-acid residues, which is also selective only for gram-negative bacteria. Those fragments with the capacity to cluster anionic lipids away from zwitterionic lipids in a membrane exhibit selective toxicity toward bacteria containing zwitterionic as well as anionic lipids in their cytoplasmic membranes but not toward bacteria with only anionic lipids. This finding allows for the prediction of the bacterial-species selectivity of certain agents and paves the way for designing new antimicrobials targeted specifically toward gram-negative bacteria.

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Increased resistance to cationic antimicrobial peptide LL-37 in methicillin-resistant strains of Staphylococcus aureus

Abstract: Clinical strains of MRSA, but not MSSA, that demonstrated an increased net charge also showed elevated resistance to LL-37, but not to hBD3.

Cited by 69 publications

References 10 publications

Methicillin-resistant Staphylococcus aureus Bacterial Nitric-oxide Synthase Affects Antibiotic Sensitivity and Skin Abscess Development

Methicillin-resistant Staphylococcus aureus Bacterial Nitric-oxide Synthase Affects Antibiotic Sensitivity and Skin Abscess Development

In Vitro Synergistic Activities of the Hybrid Antimicrobial Peptide MelitAP-27 in Combination with Conventional Antibiotics Against Planktonic and Biofilm Forming Bacteria

Lipid Segregation Explains Selective Toxicity of a Series of Fragments Derived from the Human Cathelicidin LL-37

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