Synergism of cationic antimicrobial peptide WLBU2 with antibacterial agents against biofilms of multi-drug resistant Acinetobacter baumannii and Klebsiella pneumoniae

Acinetobacter baumannii bacteremia represents a serious and increasing clinical problem due to the high mortality and treatment failures because of high rates of antibiotic resistance. Any additional new therapies for A. baumannii bacteremia would address a growing unmet medical need. ARV-1502 (designated as Chex1-Arg20 or A3-APO monomer in prior publications) is a designer proline-rich antimicrobial peptide chaperone protein inhibitor derived from insects and has demonstrated potent activity against multi-drug resistant (MDR) Gram-negative bacteria. In the current studies, we investigated the therapeutic efficacy of ARV-1502 administered intravenously (iv) alone and in combination with imipenem/cilastatin (IPM/CIL) in a mouse bacteremia model due to a MDR clinical A. baumannii strain, HUMC1. All ARV-1502 regimens (1.25, 2.5 and 5.0 mg/kg) significantly reduced bacterial density in the target tissues in a dose-dependent manner, as compared to the untreated control and IPM/CIL monotherapy (40 mg/kg) groups in the model. In addition, ARV-1502 treatment, even at the lowest dose, significantly improved survival vs. the control and IPM alone groups. As expected, IMP/CIL monotherapy had no therapeutic efficacy in the model, since the HUMC1 strain was resistant to IMP in vitro. However, the combination of ARV-1502 and IPM/CIL significantly enhanced the efficacy of ARV-1502, except the lowest dose of ARV-1502. The superior efficacy of ARV-1502 in the bacteremia model caused by MDR A. baumannii provides further support for studying this compound in severe infections caused by other MDR Gram-positive and -negative pathogens.

Download Full-text

Successful Treatment of Antibiotic-resistant, Poly-microbial Bone Infection With Bacteriophages and Antibiotics Combination

Clinical Infectious Diseases ◽

10.1093/cid/ciz222 ◽

2019 ◽

Vol 69 (11) ◽

pp. 2015-2018 ◽

Cited By ~ 32

Author(s):

Ran Nir-Paz ◽

Daniel Gelman ◽

Ayman Khouri ◽

Brittany M Sisson ◽

Joseph Fackler ◽

...

Keyword(s):

Klebsiella Pneumoniae ◽

Acinetobacter Baumannii ◽

Successful Treatment ◽

Positive Culture ◽

Multidrug Resistant ◽

Bone Infection ◽

Drug Resistant ◽

Antibiotic Resistant ◽

Extensively Drug Resistant ◽

Tissue Healing

Abstract A patient with a trauma-related left tibial infection associated with extensively drug-resistant Acinetobacter baumannii and multidrug-resistant Klebsiella pneumoniae was treated with bacteriophages and antibiotics. There was rapid tissue healing and positive culture eradication. As a result, the patient’s leg did not have to be amputated and he is undergoing rehabilitation.

Download Full-text

In vivo synthesis of monolysocardiolipin and cardiolipin by Acinetobacter baumannii phospholipase D and effect on cationic antimicrobial peptide resistance

Environmental Microbiology ◽

10.1111/1462-2920.15231 ◽

2020 ◽

Vol 22 (12) ◽

pp. 5300-5308

Author(s):

Katharina Pfefferle ◽

Patrizia Lopalco ◽

Jennifer Breisch ◽

Anna Siemund ◽

Angela Corcelli ◽

...

Keyword(s):

Antimicrobial Peptide ◽

Acinetobacter Baumannii ◽

Phospholipase D ◽

Cationic Antimicrobial Peptide ◽

Antimicrobial Peptide Resistance ◽

In Vivo Synthesis

Download Full-text

Unlocking NuriPep 1653 From Common Pea Protein: A Potent Antimicrobial Peptide to Tackle a Pan-Drug Resistant Acinetobacter baumannii

Frontiers in Microbiology ◽

10.3389/fmicb.2019.02086 ◽

2019 ◽

Vol 10 ◽

Cited By ~ 4

Author(s):

Niamh Maire Mohan ◽

Amine Zorgani ◽

Gael Jalowicki ◽

Alish Kerr ◽

Nora Khaldi ◽

...

Keyword(s):

Antimicrobial Peptide ◽

Acinetobacter Baumannii ◽

Protein A ◽

Drug Resistant ◽

Pea Protein

Download Full-text

Identification of a bacteria-produced benzisoxazole with antibiotic activity against multi-drug resistant Acinetobacter baumannii

The Journal of Antibiotics ◽

10.1038/s41429-021-00412-7 ◽

2021 ◽

Author(s):

Robert W. Deering ◽

Kristen E. Whalen ◽

Ivan Alvarez ◽

Kathryn Daffinee ◽

Maya Beganovic ◽

...

Keyword(s):

Acinetobacter Baumannii ◽

Metabolic Pathways ◽

Pathogenic Bacteria ◽

Antibacterial Agents ◽

De Novo ◽

Drug Resistant ◽

Antibacterial Effects ◽

Naturally Occurring ◽

Molecular Modeling Studies

AbstractThe emergence of multi-drug resistant pathogenic bacteria represents a serious and growing threat to national healthcare systems. Most pressing is an immediate need for the development of novel antibacterial agents to treat Gram-negative multi-drug resistant infections, including the opportunistic, hospital-derived pathogen, Acinetobacter baumannii. Herein we report a naturally occurring 1,2-benzisoxazole with minimum inhibitory concentrations as low as 6.25 μg ml−1 against clinical strains of multi-drug resistant A. baumannii and investigate its possible mechanisms of action. This molecule represents a new chemotype for antibacterial agents against A. baumannii and is easily accessed in two steps via de novo synthesis. In vitro testing of structural analogs suggest that the natural compound may already be optimized for activity against this pathogen. Our results demonstrate that supplementation of 4-hydroxybenzoate in minimal media was able to reverse 1,2-benzisoxazole’s antibacterial effects in A. baumannii. A search of metabolic pathways involving 4-hydroxybenzoate coupled with molecular modeling studies implicates two enzymes, chorismate pyruvate-lyase and 4-hydroxybenzoate octaprenyltransferase, as promising leads for the target of 3,6-dihydroxy-1,2-benzisoxazole.

Download Full-text

Comparison of colistin–carbapenem, colistin–sulbactam, and colistin plus other antibacterial agents for the treatment of extremely drug-resistant Acinetobacter baumannii bloodstream infections

European Journal of Clinical Microbiology & Infectious Diseases ◽

10.1007/s10096-014-2070-6 ◽

2014 ◽

Vol 33 (8) ◽

pp. 1311-1322 ◽

Cited By ~ 93

Author(s):

A. Batirel ◽

I. I. Balkan ◽

O. Karabay ◽

C. Agalar ◽

S. Akalin ◽

...

Keyword(s):

Acinetobacter Baumannii ◽

Antibacterial Agents ◽

Bloodstream Infections ◽

Drug Resistant

Download Full-text

Amino Acid Conjugated Polymers: Antibacterial Agents Effective against Drug-Resistant Acinetobacter baumannii with No Detectable Resistance

ACS Applied Materials & Interfaces ◽

10.1021/acsami.9b09016 ◽

2019 ◽

Vol 11 (37) ◽

pp. 33559-33572 ◽

Cited By ~ 13

Author(s):

Swagatam Barman ◽

Mohini Mohan Konai ◽

Sandip Samaddar ◽

Jayanta Haldar

Keyword(s):

Amino Acid ◽

Conjugated Polymers ◽

Acinetobacter Baumannii ◽

Antibacterial Agents ◽

Drug Resistant

Download Full-text

Potentiation of antimicrobial activity of colistin with antibiotics of different groups against multidrug- and extensively drug-resistant strains of Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa

Clinical Microbiology and Antimicrobial Chemotherapy ◽

10.36488/cmac.2020.2.128-136 ◽

2020 ◽

Vol 22 (2) ◽

pp. 128-136

Author(s):

Dmitry V. Tapalskiy ◽

T.A. Petrovskaya ◽

A.I. Kozlova ◽

Mikhail V. Edelstein

Keyword(s):

Pseudomonas Aeruginosa ◽

Antimicrobial Activity ◽

Klebsiella Pneumoniae ◽

Acinetobacter Baumannii ◽

Bactericidal Activity ◽

Drug Resistant ◽

Extensively Drug Resistant ◽

Potentiation Effect ◽

Resistant Strains ◽

Drug Resistant Strains

Objective. To reveal antibiotics being capable of potentiating the antimicrobial activity of colistin against multidrug- and extensively drug-resistant strains of Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa. Materials and Methods. The minimum inhibitory concentrations (MIC) of colistin alone and in combination with fixed concentrations of antibiotics of different groups were determined for 272 multidrug- and extensively drug-resistant strains of K. pneumoniae, A. baumannii and P. aeruginosa. Bactericidal activity of colistin, carbapenems, clarithromycin and their combinations were also determined at fixed PK/PD breakpoint concentrations of antibiotics. Results. Potentiation of colistin antibacterial activity in the presence of fixed concentration of rifampicin (0.5 mg/L) was observed as a 4–16-fold MIC decrease for K. pneumoniae and A. baumannii. In the presence of fixed concentrations of azithromycin (2 mg/L) or clarithromycin (1 mg/L), the colistin MICs decreased 64–512 times for K. pneumoniae, 4–32 times for A. baumannii, 16–64 times for P. aeruginosa. Two- or more-fold reduction of MIC of colistin in the presence of 1 mg/L clarithromycin was observed for 85.2% of K. pneumoniae, 86.3% of A. baumannii and 60.2% of P. aeruginosa strains. In the presence of 1 mg/L clarithromycin and 8 mg/L meropenem, the potentiation effect was enhanced and was observed for an even larger percent of isolates: 96.1% K. pneumoniae, 98.0% A. baumannii and 61.3% P. aeruginosa. Colistin-based combinations with clarithromycin-meropenem and clarithromycin-doripenem were bactericidal against most isolates of A. baumannii and P. aeruginosa (91.4–100%), and against colistin-sensitive K. pneumoniae (95.3%) and colistin-resistant K. pneumoniae (79.1%). Conclusions. The ability of macrolides to significantly potentiate the colistin antimicrobial activity against both colistin-sensitive and colistin-resistant strains of K. pneumoniae, A. baumannii and P. aeruginosa was shown. This potentiation effect was enhanced in the presence of carbapenems. The most potent bactericidal activity was revealed with dual and triple combinations of colistin-clarithromycin and colistinclarithromycin-carbapenems.

Download Full-text