scholarly journals Galactose-Clicked Curcumin-Mediated Reversal of Meropenem Resistance among Klebsiella pneumoniae by Targeting Its Carbapenemases and the AcrAB-TolC Efflux System

Antibiotics ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 388
Author(s):  
Shivangi Yadav ◽  
Ashish Kumar Singh ◽  
Anand K Agrahari ◽  
Akhilesh Kumar Pandey ◽  
Munesh Kumar Gupta ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Bacterial Growth ◽  
Addition Reaction ◽  
Multidrug Resistant ◽  
Water Soluble ◽  
Drug Candidate ◽  
Efflux System ◽  
New Antibiotics ◽  
Minimal Concentration ◽  
Curcumin Derivative

In over eighty years, despite successive antibiotics discoveries, the rapid advent of multidrug resistance among bacterial pathogens has jolted our misapprehension of success over them. Resistance is spreading faster than the discovery of new antibiotics/antimicrobials. Therefore, the search for better antimicrobials/additives becomes prudent. A water-soluble curcumin derivative (Curaq) was synthesised, employing a Cu (I) catalysed 1, 3-cyclo addition reaction; it has been evaluated as a potential treatment for multidrug-resistant isolates and as an antibiotic adjuvant for meropenem against hypervirulent multidrug-resistant Klebsiella pneumoniae isolates. We also investigated its solubility and effect over carbapenemase activity. Additionally, we investigated its impact on the AcrAB-TolC system. We found that Curaq inhibited bacterial growth at a minimal concentration of 16 µg/mL; at a 32 µg/mL concentration, it killed bacterial growth completely. Only nine (9.4%) Klebsiella isolates were sensitive to meropenem; however, after synergising with Curaq (8 µg/mL), 85 (88.54%) hvKP isolates became sensitive to the drug. The Curaq also inhibited the AcrAB-TolC efflux system at 1µg/mL concentration by disrupting the membrane potential and causing depolarisation. The kinetic parameters obtained also indicated its promise as a carbapenemase inhibitor. These results suggest that Curaq can be an excellent drug candidate as a broad-spectrum antibacterial and anti-efflux agent.

scholarly journals In Vitro Selection oframRandsoxRMutants Overexpressing Efflux Systems by Fluoroquinolones as Well as Cefoxitin in Klebsiella pneumoniae

2011 ◽  
Vol 55 (6) ◽  
pp. 2795-2802 ◽  
Author(s):  
Suzanne Bialek-Davenet ◽  
Estelle Marcon ◽  
Véronique Leflon-Guibout ◽  
Jean-Philippe Lavigne ◽  
Frédéric Bert ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
In Vitro Selection ◽  
Efflux Pump ◽  
Clinical Isolates ◽  
Cross Resistance ◽  
Efflux System ◽  
Content Type ◽  
New Antibiotics ◽  
Regulator Genes

ABSTRACTThe relationship between efflux system overexpression and cross-resistance to cefoxitin, quinolones, and chloramphenicol has recently been reported inKlebsiella pneumoniae. In 3 previously published clinical isolates and 17in vitromutants selected with cefoxitin or fluoroquinolones, mutations in the potential regulator genes of the AcrAB efflux pump (acrR,ramR,ramA,marR,marA,soxR,soxS, androb) were searched, and their impacts on efflux-related antibiotic cross-resistance were assessed. All mutants but 1, and 2 clinical isolates, overexpressedacrB. No mutation was detected in the regulator genes studied among the clinical isolates and 8 of the mutants. For the 9 remaining mutants, a mutation was found in theramRgene in 8 of them and in thesoxRgene in the last one, resulting in overexpression oframAandsoxS, respectively. Transformation of theramRmutants and thesoxRmutant with the wild-typeramRandsoxRgenes, respectively, abolished overexpression ofacrBandramAin theramRmutants and ofsoxSin thesoxRmutant, as well as antibiotic cross-resistance. Resistance due to efflux system overexpression was demonstrated for 4 new antibiotics: cefuroxime, cefotaxime, ceftazidime, and ertapenem. This study shows that theramRandsoxRgenes control the expression of efflux systems inK. pneumoniaeand suggests the existence of efflux pumps other than AcrAB and of other loci involved in the regulation of AcrAB expression.

scholarly journals Analysis of the Oxidative Stress Regulon Identifies soxS as a Genetic Target for Resistance Reversal in Multidrug-Resistant Klebsiella pneumoniae

mBio ◽  
2021 ◽  
Author(s):  
João Anes ◽  
Katherine Dever ◽  
Athmanya Eshwar ◽  
Scott Nguyen ◽  
Yu Cao ◽  
...  
Keyword(s):  
Public Health ◽  
Oxidative Stress ◽  
Antimicrobial Resistance ◽  
Klebsiella Pneumoniae ◽  
Global Health ◽  
Multidrug Resistant ◽  
Content Type ◽  
Resistance Reversal ◽  
New Antibiotics ◽  
Global Health Challenge

Antimicrobial resistance is a global health challenge. Few new antibiotics have been developed for use over the years, and preserving the efficacy of existing compounds is an important step to protect public health. This paper describes a study that examines the effects of exogenously induced oxidative stress on K. pneumoniae and uncovers a target that could be useful to harness as a strategy to mitigate resistance.

Multidrug-resistant mcr-1 gene-positive Klebsiella pneumoniae ST307 causing urinary tract infection in a cat

2021 ◽  
Author(s):  
Alessandra Tammy Hayakawa Ito de Sousa ◽  
Marco Túlio dos Santos Costa ◽  
Herica Makino ◽  
Stéfhano Luis Cândido ◽  
Isabela de Godoy Menezes ◽  
...  
Keyword(s):  
Urinary Tract Infection ◽  
Urinary Tract ◽  
Tract Infection ◽  
Klebsiella Pneumoniae ◽  
Multidrug Resistant

scholarly journals Virulent and multidrug‐resistant Klebsiella pneumoniae from clinical samples in Balochistan

2021 ◽  
Author(s):  
Sareeen Fatima ◽  
Faiza Liaqat ◽  
Ali Akbar ◽  
Muhammad Sahfee ◽  
Abdul Samad ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Multidrug Resistant ◽  
Clinical Samples

scholarly journals Amphipathic Peptide Antibiotics with Potent Activity against Multidrug-Resistant Pathogens

Pharmaceutics ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 438
Author(s):  
Jingru Shi ◽  
Chen Chen ◽  
Dejuan Wang ◽  
Ziwen Tong ◽  
Zhiqiang Wang ◽  
...  
Keyword(s):  
Membrane Damage ◽  
Multidrug Resistant ◽  
Peptide Antibiotics ◽  
Biofilm Inhibition ◽  
Amphipathic Peptide ◽  
Host Defense Peptides ◽  
Gram Negative ◽  
Wide Range ◽  
New Antibiotics ◽  
Low Toxicity

The emergence and prevalence of multidrug-resistant (MDR) bacteria have posed a serious threat to public health. Of particular concern are methicillin-resistant Staphylococcus aureus (MRSA) and blaNDM, mcr-1 and tet(X)-positive Gram-negative pathogens. The fact that few new antibiotics have been approved in recent years exacerbates this global crisis, thus, new alternatives are urgently needed. Antimicrobial peptides (AMPs) originated from host defense peptides with a wide range of sources and multiple functions, are less prone to achieve resistance. All these characteristics laid the foundation for AMPs to become potential antibiotic candidates. In this study, we revealed that peptide WW307 displayed potent antibacterial and bactericidal activity against MDR bacteria, including MRSA and Gram-negative bacteria carrying blaNDM-5, mcr-1 or tet(X4). In addition, WW307 exhibited great biofilm inhibition and eradication activity. Safety and stability experiments showed that WW307 had a strong resistance against various physiological conditions and displayed relatively low toxicity. Mechanistic experiments showed that WW307 resulted in membrane damage by selectively targeting bacterial membrane-specific components, including lipopolysaccharide (LPS), phosphatidylglycerol (PG), and cardiolipin (CL). Moreover, WW307 dissipated membrane potential and triggered the production of reactive oxygen species (ROS). Collectively, these results demonstrated that WW307 represents a promising candidate for combating MDR pathogens.

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