Characterization of Corosolic Acid as a KPC-2 Inhibitor That Increases the Susceptibility of KPC-2-Positive Bacteria to Carbapenems

Zhou, Yonglin; Lv, Xiaoyi; Chen, Meishan; Guo, Yan; Ding, Rui; Liu, Bin; Deng, Xuming

doi:10.3389/fphar.2020.01047

Cited by 10 publications

(5 citation statements)

References 36 publications

(42 reference statements)

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“…Hence, in this study, celastrol was evaluated as potential inhibitor of carbapenemases to restore the activity of meropenem on CRK. Our results showed that celastrol had activity on all tested classes of carbapenemases (KPC, NDM, OXA and VIM-2), while Zhou et al [ 17 ] reported activity against KPC enzyme only. Moreover, the study of Zhou and coworkers used only a standard E .…”

Section: Discussionmentioning

confidence: 52%

“…It does not show in vitro activity against class-D OXA-48 β-lactamases but has potent activity against class-A and class-C β-lactamases [ 49 ]. It was reported that triterpenoids such as corosolic acid and polycyclic terpene acids such as oleanolic acid had β-lactamase inhibitory activity [ 17 ]. Celastrol has similar chemical structure and biological activity to corosolic and oleanolic acid.…”

Section: Discussionmentioning

confidence: 99%

“…However, pentacyclic triterpenoids (e.g., corosolic acid) and polycyclic terpene (e.g., oleanolic acid) were reported as β-lactamase inhibitors. Based on similarities in chemical structure and biological activities [ 17 ], celastrol is thought to show a similar activity as a potential β-lactamase inhibitor. This study aims to evaluate the antibacterial activity of celastrol against CRK and to investigate its carbapenemase-inhibitory potential.…”

Section: Introductionmentioning

confidence: 99%

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In vitro activity of celastrol in combination with thymol against carbapenem-resistant Klebsiella pneumoniae isolates

et al. 2022

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Klebsiella pneumoniae is an opportunistic pathogen causing nosocomial and community-acquired infections. Klebsiella has developed resistance against antimicrobials including the last resort class; carbapenem. Currently, treatment options for carbapenem-resistant-Klebsiella (CRK) are very limited. This study aims to restore carbapenem effectiveness against CRK using celastrol and thymol. Clinical Klebsiella isolates were identified using biochemical and molecular methods. Antimicrobial susceptibility was determined using disk-diffusion method. Carbapenemase-production was tested phenotypically and genotypically. Celastrol and thymol-MICs were determined and the carbapenemase-inhibitory effect of sub-MICs was investigated. Among 85 clinical Klebsiella isolates, 72 were multi-drug-resistant and 43 were meropenem-resistant. Phenotypically, 39 isolates were carbapenemase-producer. Genotypically, blaNDM1 was detected in 35 isolates, blaVIM in 17 isolates, blaOXA in 18 isolates, and blaKPC was detected only in 6 isolates. Celastrol showed significant inhibitory effect against carbapenemase-hydrolytic activity. Meropenem-MIC did not decrease in presence of celastrol, only 2-fold decrease was observed with thymol, while 4–64 fold decrease was observed when meropenem was combined with both celastrol and thymol. Furthermore, thymol increased CRK cell wall-permeability. Molecular docking revealed that celastrol is superior to thymol for binding to KPC and VIM-carbapenemase. Our study showed that celastrol is a promising inhibitor of multiple carbapenemases. While meropenem-MIC were not affected by celastrol alone and decreased by only 2-folds with thymol, it decreased by 4–64 folds in presence of both celastrol and thymol. Thymol increases the permeability of CRK-envelope to celastrol. The triple combination (meropenem/celastrol/thymol) could be useful for developing more safe and effective analogues to restore the activity of meropenem and other β-lactams.

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Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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In vitro activity of celastrol in combination with thymol against carbapenem-resistant Klebsiella pneumoniae isolates

et al. 2022

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“…Corosolic acid ( 18 ) has been reported to exhibit activity against the formation of P. aeruginosa biofilm, and showed synergistic effects with ciprofloxacin, enhancing the susceptibility of bacterial biofilm to this antibiotic [ 53 ]. In addition, corosolic acid has demonstrated the ability to increase the susceptibility of resistant Klebsiella pneumoniae to carbapenem antibiotics [ 54 ]. In terms of chemical composition, the SHP phase exhibited the least complex profile among the analyzed samples, and shares compounds 1, 3, 10, 11 and 18 with the SCP phase.…”

Section: Discussionmentioning

confidence: 99%

Medicinal plant Miconia albicans synergizes with ampicillin and ciprofloxacin against multi-drug resistant Acinetobacter baumannii and Staphylococcus aureus

de Jesus,

Silva Trentin,

Barros

et al. 2023

BMC Complement Med Ther

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Background Given the rising occurrence of antibiotic resistance due to the existence and ongoing development of resistant bacteria and phenotypes, the identification of new treatments and sources of antimicrobial agents is of utmost urgency. An important strategy for tackling bacterial resistance involves the utilization of drug combinations, and natural products derived from plants hold significant potential as a rich source of bioactive compounds that can act as effective adjuvants. This study, therefore, aimed to assess the antibacterial potential and the chemical composition of Miconia albicans, a Brazilian medicinal plant used to treat various diseases. Methods Ethanolic extracts from leaves and stems of M. albicans were obtained and subsequently partitioned to give the corresponding hexane, chloroform, ethyl acetate, and hydromethanolic phases. All extracts and phases had their chemical constitution investigated by HPLC–DAD-MS/MS and GC–MS and were assessed for their antibiofilm and antimicrobial efficacy against Staphylococcus aureus. Furthermore, their individual effects and synergistic potential in combination with antibiotics were examined against clinical strains of both S. aureus and Acinetobacter baumannii. In addition, 10 isolated compounds were obtained from the leaves phases and used for confirmation of the chemical profiles and for antibacterial assays. Results Based on the chemical profile analysis, 32 compounds were successfully or tentatively identified, including gallic and ellagic acid derivatives, flavonol glycosides, triterpenes and pheophorbides. Extracts and phases obtained from the medicinal plant M. albicans demonstrated synergistic effects when combined with the commercial antibiotics ampicillin and ciprofloxacin, against multi-drug resistant bacteria S. aureus and A. baumannii, restoring their antibacterial efficacy. Extracts and phases also exhibited antibiofilm property against S. aureus. Three key compounds commonly found in the samples, namely gallic acid, quercitrin, and corosolic acid, did not exhibit significant antibacterial activity when assessed individually or in combination with antibiotics against clinical bacterial strains. Conclusions Our findings reveal that M. albicans exhibits remarkable adjuvant potential for enhancing the effectiveness of antimicrobial drugs against resistant bacteria.

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“…Compounds from natural sources were reported as BLIs in various studies [ 18 – 20 ]. One of the natural compounds that could exhibit a promising antibacterial application is coumarin.…”

Section: Introductionmentioning

confidence: 99%

Phenotypic, molecular, and in silico characterization of coumarin as carbapenemase inhibitor to fight carbapenem-resistant Klebsiella pneumoniae

Abdel-Halim,

El-Ganiny,

Mansour

et al. 2024

BMC Microbiol

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Background Carbapenems represent the first line treatment of serious infections caused by drug-resistant Klebsiella pneumoniae. Carbapenem-resistant K. pneumoniae (CRKP) is one of the urgent threats to human health worldwide. The current study aims to evaluate the carbapenemase inhibitory potential of coumarin and to test its ability to restore meropenem activity against CRKP. Disk diffusion method was used to test the antimicrobial susceptibility of K. pneumoniae clinical isolates to various antibiotics. Carbapenemase genes (NDM-1, VIM-2, and OXA-9) were detected using PCR. The effect of sub-MIC of coumarin on CRKP isolates was performed using combined disk assay, enzyme inhibition assay, and checkerboard assay. In addition, qRT-PCR was used to estimate the coumarin effect on expression of carbapenemase genes. Molecular docking was used to confirm the interaction between coumarin and binding sites within three carbapenemases. Results K. pneumoniae clinical isolates were found to be multi-drug resistant and showed high resistance to meropenem. All bacterial isolates harbor at least one carbapenemase-encoding gene. Coumarin significantly inhibited carbapenemases in the crude periplasmic extract of CRKP. The checkerboard assay indicated that coumarin-meropenem combination was synergistic exhibiting a fractional inhibitory concentration index ≤ 0.5. In addition, qRT-PCR results revealed that coumarin significantly decreased carbapenemase-genes expression. Molecular docking revealed that the binding energies of coumarin to NDM1, VIM-2, OXA-48 and OXA-9 showed a free binding energy of -7.8757, -7.1532, -6.2064 and − 7.4331 Kcal/mol, respectively. Conclusion Coumarin rendered CRKP sensitive to meropenem as evidenced by its inhibitory action on hydrolytic activity and expression of carbapenemases. The current findings suggest that coumarin could be a possible solution to overcome carbapenems resistance in CRKP.

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Characterization of Corosolic Acid as a KPC-2 Inhibitor That Increases the Susceptibility of KPC-2-Positive Bacteria to Carbapenems

Cited by 10 publications

References 36 publications

In vitro activity of celastrol in combination with thymol against carbapenem-resistant Klebsiella pneumoniae isolates

In vitro activity of celastrol in combination with thymol against carbapenem-resistant Klebsiella pneumoniae isolates

Medicinal plant Miconia albicans synergizes with ampicillin and ciprofloxacin against multi-drug resistant Acinetobacter baumannii and Staphylococcus aureus

Phenotypic, molecular, and in silico characterization of coumarin as carbapenemase inhibitor to fight carbapenem-resistant Klebsiella pneumoniae

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