Protective effects of the combination of α-helical antimicrobial peptides and rifampicin in three rat models of Pseudomonas aeruginosa infection

Cirioni, Oscar; Silvestri, Carmela; Ghiselli, Roberto; Orlando, Fiorenza; Riva, Alessandra; Mocchegiani, Federico; Chiodi, Leonardo; Castelletti, Sefora; Gabrielli, Eleonora; Saba, Vittorio; Scalise, Giorgio; Giacometti, Andrea

doi:10.1093/jac/dkn393

Cited by 60 publications

(43 citation statements)

References 30 publications

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“…as well (19). Our observations are consistent with the work of Cirioni et al, who similarly reported a synergistic effect between rifampin and ␣-helical AMPs (magainin II and cecropin A) in Pseudomonas aeruginosa infection models in rats (25). It was hypothesized that AMPs allow rifampin, an RNA polymerase inhibitor, to access its intracellular target by permeabilization of the bacterial membrane (19,36).…”

Section: Discussionsupporting

confidence: 91%

“…Infected mice were treated once a day with eCATH1 (1 mg/kg body weight; group I), rifampin (10 mg/kg body weight; group II), a combination of both in the same concentrations as mentioned above (group III), or the same volume of isotonic sodium chloride (control group) for 7 days. The doses, periodicities, and route of injections were chosen based on previous reports (24)(25)(26). Five mice per group were sacrificed 1, 4, and 8 days postinfection (i.e., at the start, middle, and end of treatment), and their spleens and livers were aseptically removed.…”

Section: Methodsmentioning

confidence: 99%

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The Equine Antimicrobial Peptide eCATH1 Is Effective against the Facultative Intracellular Pathogen Rhodococcus equi in Mice

Schlusselhuber¹,

Torelli

Martini

et al. 2013

Antimicrob Agents Chemother

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f Rhodococcus equi, the causal agent of rhodococcosis, is a major pathogen of foals and is also responsible for severe infections in immunocompromised humans. Of great concern, strains resistant to currently used antibiotics have emerged. As the number of drugs that are efficient in vivo is limited because of the intracellular localization of the bacterium inside macrophages, new active but cell-permeant drugs will be needed in the near future. In the present study, we evaluated, by in vitro and ex vivo experiments, the ability of the alpha-helical equine antimicrobial peptide eCATH1 to kill intracellular bacterial cells. Moreover, the therapeutic potential of the peptide was assessed in experimental rhodococcosis induced in mice, while the in vivo toxicity was evaluated by behavioral and histopathological analysis. The study revealed that eCATH1 significantly reduced the number of bacteria inside macrophages. Furthermore, the bactericidal potential of the peptide was maintained in vivo at doses that appeared to have no visible deleterious effects for the mice even after 7 days of treatment. Indeed, daily subcutaneous injections of 1 mg/kg body weight of eCATH1 led to a significant reduction of the bacterial load in organs comparable to that obtained after treatment with 10 mg/kg body weight of rifampin. Interestingly, the combination of the peptide with rifampin showed a synergistic interaction in both ex vivo and in vivo experiments. These results emphasize the therapeutic potential that eCATH1 represents in the treatment of rhodococcosis.

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Section: Discussionsupporting

confidence: 91%

Section: Methodsmentioning

confidence: 99%

The Equine Antimicrobial Peptide eCATH1 Is Effective against the Facultative Intracellular Pathogen Rhodococcus equi in Mice

Schlusselhuber¹,

Torelli

Martini

et al. 2013

Antimicrob Agents Chemother

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“…AMPs that target membranes are less likely to be rendered ineffective by resistance, because redesigning the microbial membrane architecture cannot be achieved by simple mutations (13,17). Furthermore, combinations of AMPs with traditional antibiotics may achieve enhanced or synergistic activity against bacterial pathogens (18)(19)(20).…”

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confidence: 99%

Synergistic Efficacy of Aedes aegypti Antimicrobial Peptide Cecropin A2 and Tetracycline against Pseudomonas aeruginosa

Zheng

Tharmalingam

et al. 2017

Antimicrob Agents Chemother

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The increasing prevalence of antibiotic resistance has created an urgent need for alternative drugs with new mechanisms of action. Antimicrobial peptides (AMPs) are promising candidates that could address the spread of multidrugresistant bacteria, either alone or in combination with conventional antibiotics. We studied the antimicrobial efficacy and bactericidal mechanism of cecropin A2, a 36-residue ␣-helical cationic peptide derived from Aedes aegypti cecropin A, focusing on the common pathogen Pseudomonas aeruginosa. The peptide showed little hemolytic activity and toxicity toward mammalian cells, and the MICs against most clinical P. aeruginosa isolates were 32 to 64 g/ml, and its MICs versus other Gramnegative bacteria were 2 to 32 g/ml. Importantly, cecropin A2 demonstrated synergistic activity against P. aeruginosa when combined with tetracycline, reducing the MICs of both agents by 8-fold. The combination was also effective in vivo in the P. aeruginosa/Galleria mellonella model (P Ͻ 0.001). We found that cecropin A2 bound to P. aeruginosa lipopolysaccharides, permeabilized the membrane, and interacted with the bacterial genomic DNA, thus facilitating the translocation of tetracycline into the cytoplasm. In summary, the combination of cecropin A2 and tetracycline demonstrated synergistic antibacterial activity against P. aeruginosa in vitro and in vivo, offering an alternative approach for the treatment of P. aeruginosa infections.KEYWORDS antimicrobial activity, antimicrobial peptide, cecropin A2, Pseudomonas aeruginosa, tetracycline P seudomonas aeruginosa is a Gram-negative opportunistic bacterial pathogen that causes life-threatening infections with high rates of mortality (1-3). It is associated with nosocomial pneumonia, wound infections, bacteremia, and sepsis among patients with various underlying diseases, including cystic fibrosis, HIV/AIDS, and cancer (4). Antibiotic therapy is challenging in this setting because clinical strains of P. aeruginosa often show extensive intrinsic resistance to a wide range of antimicrobial agents, including tetracyclines, ␤-lactams, aminoglycosides, and fluoroquinolones (5). This intrinsic resistance has generally been attributed to the low membrane permeability of P. aeruginosa, up to 100 times lower than that of Escherichia coli (6). P. aeruginosa can also withstand antibiotics that attack the outer membrane through the efficient deployment of transmembrane efflux pumps, preventing contact between the antibiotics and their intracellular targets (7-11).The ubiquitous and relentless clinical challenge of drug resistance has created a

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“…Magainin II shows a synergistic effect with cecropin peptides (cecropin A and B) 9 , inhibit cell proliferation and viability in a dose dependent fashion in bladder cancer cells 10 . However, there is no report on the use of magainin peptides for treatment against colorectal cancer (CRC).…”

Section: Introductionmentioning

confidence: 99%

Untitled

2016

IJPSR

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Antimicrobial peptides (AMP) showed a broad spectrum of cytotoxic activity against cancer cells, which could provide a new class of anticancer drugs. In this study, we have evaluated the cytotoxic and apoptotic activity of magainin II, an AMP compared with 5-Fluorouracil (5-FU) in colo320 DM cancer cells, and magainin II cytotoxicity was assessed on vero cell line by MTT. The cells cultured in the presence or absence of magainin II and 5-FU. The magainin II inhibited cell viability in dose dependent manner was quantified by MTT assay. The IC 50 of magainin II was found to be 89.3nM and at this concentration the cytotoxicity was not observed in vero cell line. The cytotoxicity of the magainin II was further confirmed by lactate dehydrogenase (LDH) assay and neutral red uptake assay (NRU). Apoptosis induction was verified by DNA fragmentation analysis. The morphological changes in colo 320 DM cells was measured by DAPI and acridine orange/ethidium bromide staining, showed nuclear condensation, and this substantiates the apoptotic action of magainin II. The cell cycle analysis by FACS revealed that there was a accumulation of cells at G0/G1 phase in magainin II treated cells. Overall, these results revealed that magainin II has selective cytotoxicity in cancer cells and has the potential to induce apoptosis. Magainin II may offer a novel and effective therapeutic candidate in the treatment of colon cancer with potentially low cytotoxic effects on normal cells. These findings highlight the importance of magainin II as a drug capable of exerting an in vitro antitumoral activity by triggering apoptosis.

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Protective effects of the combination of α-helical antimicrobial peptides and rifampicin in three rat models of Pseudomonas aeruginosa infection

Abstract: Our results highlight the potential usefulness of these combinations that provide future therapeutic alternatives in P. aeruginosa infections.

Cited by 60 publications

References 30 publications

The Equine Antimicrobial Peptide eCATH1 Is Effective against the Facultative Intracellular Pathogen Rhodococcus equi in Mice

The Equine Antimicrobial Peptide eCATH1 Is Effective against the Facultative Intracellular Pathogen Rhodococcus equi in Mice

Synergistic Efficacy of Aedes aegypti Antimicrobial Peptide Cecropin A2 and Tetracycline against Pseudomonas aeruginosa

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