Structure-activity relationship-based screening of antibiotics against Gram-negative Acinetobacter baumannii

Lee, Jee Young; Jeong, Min-Cheol; Jeon, Dasom; Lee, Yeongjun; Lee, Woo Cheol; Kim, Yangmee

doi:10.1016/j.bmc.2016.11.001

Cited by 15 publications

(5 citation statements)

References 28 publications

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“…P. acnes KAS III C122A was expressed, purified and used to measure the binding constant of phloretin, which was compared to that of acyl-CoA and P. acnes KAS III C122A [30]. Phloretin was titrated against 10 μM JNK1 or 3 μM P. acnes KAS III solution, and fluorescence quantum yields were calculated by measuring tryptophan emission on a RF-5301PC Spectrofluorophotometer (Shimadzu, Kyoto, Japan) [48].…”

Section: Methodsmentioning

confidence: 99%

Target Proteins of Phloretin for Its Anti-Inflammatory and Antibacterial Activities Against Propionibacterium acnes-Induced Skin Infection

et al. 2019

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Phloretin is a natural chalcone with antibacterial and anti-inflammatory effects. This study investigated the anti-acne activity of phloretin against Propionibacterium acnes-induced skin infection and the potential target proteins of its anti-inflammatory and antibacterial effects. Phloretin potently inhibited the growth of P. acnes and P. acnes-induced Toll-like receptor (TLR) 2-mediated inflammatory signaling in human keratinocytes. Secreted embryonic alkaline phosphatase assay confirmed that the anti-inflammatory activity of phloretin is associated with the P. acnes-stimulated TLR2-mediated NF-κB signaling pathway. Phloretin significantly decreased the level of phosphorylated c-Jun N-terminal kinase (JNK), showing a binding affinity of 1.184 × 10−5 M−1. We also found that phloretin binds with micromolar affinity to P. acnes β-ketoacyl acyl carrier protein (ACP) synthase III (KAS III), an enzyme involved in fatty acid synthesis. Conformation-sensitive native polyacrylamide gel electrophoresis showed that phloretin reduced KAS III-mediated 3-ketoacyl ACP production by over 66%. A docking study revealed that phloretin interacts with the active sites of JNK1 and KAS III, suggesting their involvement in P. acnes-induced inflammation and their potential as targets for the antibacterial activity of phloretin. These results demonstrate that phloretin may be useful in the prevention or treatment of P. acnes infection.

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Section: Methodsmentioning

confidence: 99%

Target Proteins of Phloretin for Its Anti-Inflammatory and Antibacterial Activities Against Propionibacterium acnes-Induced Skin Infection

et al. 2019

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“…Pyrazole derivatives are another class of pharmacologically important molecules known for their wide range of therapeutic properties including antimicrobial activities [18,19,20]. Likewise, hydrazone derivatives are known for their wide range of biological activities including antibacterial properties; e.g., rifampicin, an approved drug to treat tuberculosis [21,22].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Hydrazone Derivatives of 4-[4-Formyl-3-(2-oxochromen-3-yl)pyrazol-1-yl]benzoic acid as Potent Growth Inhibitors of Antibiotic-resistant Staphylococcus aureus and Acinetobacter baumannii

et al. 2019

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Microbial resistance to drugs is an unresolved global concern, which is present in every country. Developing new antibiotics is one of the guidelines of the Centers for Disease Control and Preventions (CDC) to combat bacterial resistance to drugs. Based on our lead molecules, we report the synthesis and antimicrobial studies of 27 new pyrazole derivatives. These new coumarin-pyrazole-hydrazone hybrids are readily synthesized from commercially available starting materials and reagents using benign reaction conditions. All the synthesized molecules were tested against 14 Gram-positive and Gram-negative bacterial strains. Several of these molecules have been found to be potent growth inhibitors of several strains of these tested bacteria with minimum inhibitory concentrations as low as 1.56 μg/mL. Furthermore, active molecules are non-toxic in in vitro and in vivo toxicity studies.

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“…These screens resulted in the discovery of many antibiotics exhibiting both broad spectrum, such as streptomycin (19), and mycobacterium-specific activity, including isoniazid, pyrazinamide, ethionamide, ethambutol (4), and bedaquiline (20). Recently, Gramspecific (21)(22)(23)(24) and pathogen-specific (25,26) antibiotic discovery were also proven to be successful, leading to the identification of narrow spectrum compounds, including some that are active only against A. baumannii (27)(28)(29). As more candidate compounds are revealed through screening, there will be a need for better methods to elucidate their mechanism of action (MOA) in A. baumannii.…”

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confidence: 99%

Bacterial Cytological Profiling as a Tool To Study Mechanisms of Action of Antibiotics That Are Active against Acinetobacter baumannii

Htoo

Brumage

Chaikeeratisak

et al. 2019

Antimicrob Agents Chemother

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An increasing number of multidrug-resistant Acinetobacter baumannii (MDR-AB) infections have been reported worldwide, posing a threat to public health. The establishment of methods to elucidate the mechanism of action (MOA) of A. baumannii-specific antibiotics is needed to develop novel antimicrobial therapeutics with activity against MDR-AB. We previously developed bacterial cytological profiling (BCP) to understand the MOA of compounds in Escherichia coli and Bacillus subtilis. Given how distantly related A. baumannii is to these species, it was unclear to what extent it could be applied. Here, we implemented BCP as an antibiotic MOA discovery platform for A. baumannii. We found that the BCP platform can distinguish among six major antibiotic classes and can also subclassify antibiotics that inhibit the same cellular pathway but have different molecular targets. We used BCP to show that the compound NSC145612 inhibits the growth of A. baumannii via targeting RNA transcription. We confirmed this result by isolating and characterizing resistant mutants with mutations in the rpoB gene. Altogether, we conclude that BCP provides a useful tool for MOA studies of antibacterial compounds that are active against A. baumannii.

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Structure-activity relationship-based screening of antibiotics against Gram-negative Acinetobacter baumannii

Cited by 15 publications

References 28 publications

Target Proteins of Phloretin for Its Anti-Inflammatory and Antibacterial Activities Against Propionibacterium acnes-Induced Skin Infection

Target Proteins of Phloretin for Its Anti-Inflammatory and Antibacterial Activities Against Propionibacterium acnes-Induced Skin Infection

Synthesis of Hydrazone Derivatives of 4-[4-Formyl-3-(2-oxochromen-3-yl)pyrazol-1-yl]benzoic acid as Potent Growth Inhibitors of Antibiotic-resistant Staphylococcus aureus and Acinetobacter baumannii

Bacterial Cytological Profiling as a Tool To Study Mechanisms of Action of Antibiotics That Are Active against Acinetobacter baumannii

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