Activity of Cecropin A-Melittin Hybrid Peptides against Colistin-Resistant Clinical Strains of
            <i>Acinetobacter baumannii</i>
            : Molecular Basis for the Differential Mechanisms of Action

Saugar, José María; Rodríguez-Hernández, María Jesús; Torre, Beatriz G. de la; Pachón-Ibáñez, María Eugenia; Fernández‐Reyes, María José; Andreu, David; Pachón, Jerónimo; Rivas, Luís

doi:10.1128/aac.50.4.1251-1256.2006

Cited by 83 publications

(70 citation statements)

References 49 publications

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“…This mechanistic difference is clinically attractive and is well illustrated by the susceptibility of polymyxin-resistant A. baumannii strains to such peptides (480,562). Bactericidal activity against A. baumannii, using both in vitro (4,193,448,479,480,562) and in vivo (56, 125) models, has been reported. Combination studies, as determined by fractional inhibitory indexes, demonstrated that magainin II acted synergistically with ␤-lactams against multidrug-resistant A. baumannii but that four other peptides showed no synergy (192).…”

Section: Vol 21 2008mentioning

confidence: 99%

“…Furthermore, in a mouse peritoneal infection model using E. coli, C 12 K-7␣ 8 prevented mortality similar to imipenem and ciprofloxacin, whereas conventional peptides did not (448). Overall, antimicrobial peptides have demonstrated great potential and may provide a feasible alternative for treatment of A. baumannii infections, including those caused by polymyxin-resistant A. baumannii (480,562). Toxicity and efficacy data from human studies are awaited.…”

Section: Vol 21 2008mentioning

confidence: 99%

“…Justifiably, significant attention is being directed toward eukaryotic antimicrobial peptides, which are ubiquitous elements of the innate immune response in a variety of invertebrate, plant, and animal species (64). These cationic peptides act primarily by disturbing the cell membranes and share a similar structure and charge profile with the polymyxins, but the final steps in pathogen lethality have been shown to be different (479,480). This mechanistic difference is clinically attractive and is well illustrated by the susceptibility of polymyxin-resistant A. baumannii strains to such peptides (480,562).…”

Section: Vol 21 2008mentioning

confidence: 99%

“…These cationic peptides act primarily by disturbing the cell membranes and share a similar structure and charge profile with the polymyxins, but the final steps in pathogen lethality have been shown to be different (479,480). This mechanistic difference is clinically attractive and is well illustrated by the susceptibility of polymyxin-resistant A. baumannii strains to such peptides (480,562). Bactericidal activity against A. baumannii, using both in vitro (4,193,448,479,480,562) and in vivo (56, 125) models, has been reported.…”

Section: Vol 21 2008mentioning

confidence: 99%

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Acinetobacter baumannii : Emergence of a Successful Pathogen

2008

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SUMMARY Acinetobacter baumannii has emerged as a highly troublesome pathogen for many institutions globally. As a consequence of its immense ability to acquire or upregulate antibiotic drug resistance determinants, it has justifiably been propelled to the forefront of scientific attention. Apart from its predilection for the seriously ill within intensive care units, A. baumannii has more recently caused a range of infectious syndromes in military personnel injured in the Iraq and Afghanistan conflicts. This review details the significant advances that have been made in our understanding of this remarkable organism over the last 10 years, including current taxonomy and species identification, issues with susceptibility testing, mechanisms of antibiotic resistance, global epidemiology, clinical impact of infection, host-pathogen interactions, and infection control and therapeutic considerations.

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Section: Vol 21 2008mentioning

confidence: 99%

Section: Vol 21 2008mentioning

confidence: 99%

Section: Vol 21 2008mentioning

confidence: 99%

Section: Vol 21 2008mentioning

confidence: 99%

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Acinetobacter baumannii : Emergence of a Successful Pathogen

2008

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“…Accordingly, we found that cecropin A2 induced a concentrationdependent DNA-binding ability during electrophoresis, indicating that the peptide may kill bacterial cells by first permeabilizing the membrane and then targeting intracellular components, including the genomic DNA (44). Like other members of the cecropin family, the linear cationic ␣-helical peptide cecropin A2 is therefore likely to interact with the negatively charged components of the bacterial membrane to disrupt its integrity (16,45) before entering the cell and interacting directly with the DNA. When combined with tetracycline, the ability of cecropin A2 to permeabilize the cell facilitates the internalization of the antibiotic, and thus potentiating its ability to inhibit protein synthesis.…”

Section: Zheng Et Al Antimicrobial Agents and Chemotherapymentioning

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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Antimicrobial Peptides

Marcos¹,

Manzanares²

2011

Antimicrobial Polymers

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Antimicrobial peptides (AMPs), important effector molecules of the innate immune system, also provide templates for designing novel antibiotics. Protegrin, an especially potent AMP found in porcine leukocytes, was recently shown to form octameric transmembrane pores. We have employed a combination of experiments and models spanning length scales from the atomistic to the cellular level in order to elucidate the microbicidal mechanism of protegrin. Comparison of the modeling and experimental data suggests that approximately 10-100 protegrin pores are necessary to explain the observed rates of potassium leakage and Escherichia coli death in exponential-phase bacteria. The kinetics of viability loss suggest that bacterial death results largely from uncontrolled ion exchange processes and decay of transmembrane potential. However, ion exchange processes alone cannot account for the experimentally observed cell swelling and osmotic lysis-a redundant ''overkill'' mechanism most likely to occur in locales with high protegrin concentrations. Although our study is limited to protegrin and E. coli, the timeline of events described herein is likely shared by other AMPs that act primarily by permeabilizing microbial membranes. This work provides many of the missing links in describing antimicrobial action, as well as providing a quantitative connection between several previous experimental and simulation studies of protegrin.

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Activity of Cecropin A-Melittin Hybrid Peptides against Colistin-Resistant Clinical Strains of Acinetobacter baumannii : Molecular Basis for the Differential Mechanisms of Action

Cited by 83 publications

References 49 publications

Acinetobacter baumannii : Emergence of a Successful Pathogen

Acinetobacter baumannii : Emergence of a Successful Pathogen

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

Antimicrobial Peptides

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