Discovery of Novel Pleuromutilin Derivatives as Potent Antibacterial Agents for the Treatment of MRSA Infection

Fang, Han-Qing; Zeng, Jie; Wang, Shou-Kai; Wang, Xiao; Chen, Fang; Li, Bo; Liu, Jie; Jin, Zhen; Liu, Yahong; Tang, You‐Zhi

doi:10.3390/molecules27030931

Cited by 6 publications

(5 citation statements)

References 41 publications

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“…It should be noted that results obtained with microsomes cannot be used for quantitative estimations of in vivo biotransformation [ 71 ]. As TIA was reported to have a high inhibitory effect on CYP3A4 in human liver microsomes with an IC 50 of 1.6 μM [ 69 ], data obtained in the present study exhibited that the pharmacokinetic parameters, such as AUC but not V d , CL, MRT, of AFB1 were altered after oral co-administration with TIA in chicken.…”

Section: Discussionmentioning

confidence: 46%

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Exploration of Cytochrome P450-Related Interactions between Aflatoxin B1 and Tiamulin in Broiler Chickens

Sun,

Lootens,

Kabeta

et al. 2024

Toxins

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Poultry may face simultaneous exposure to aflatoxin B1 (AFB1) and tiamulin (TIA), given mycotoxin contamination and antibiotic use. As both mycotoxins and antibiotics can affect cytochrome P450 enzymes (CYP450), our study aimed to explore their interaction. We developed UHPLC-MS/MS methods for the first-time determination of the interaction between TIA and AFB1 in vitro and in vivo in broiler chickens. The inhibition assay showed the half maximal inhibitory concentration (IC50) values of AFB1 and TIA in chicken liver microsomes are more than 7.6 μM, indicating an extremely weak inhibitory effect on hepatic enzymes. Nevertheless, the oral TIA pharmacokinetic results indicated that AFB1 significantly increased the area under the plasma concentration-time curve (AUClast) of TIA by 167% (p < 0.01). Additionally, the oral AFB1 pharmacokinetics revealed that TIA increased the AUClast and mean residence time (MRT) of AFB1 by 194% (p < 0.01) and 136%, respectively. These results suggested that the observed inhibition may be influenced by other factors, such as transport. Therefore, it is meaningful to further explore transport and other enzymes, involved in the interaction between AFB1 and TIA. Furthermore, additional clinical studies are necessary to thoroughly assess the safety of co-exposure with mycotoxins and antibiotics.

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Section: Discussionmentioning

confidence: 46%

“…Pleuromutilin derivatives like TIA can inhibit CYP3A4 activity with an IC 50 of 1.6 μM and showed strong inhibition to CYP450 enzymes [ 69 ]. In contrast, the IC 50 values for CYP2A6 and CYP2E1 were 7.6 μM and 47.6 μM in CLM in this study, respectively.…”

Section: Discussionmentioning

confidence: 99%

Exploration of Cytochrome P450-Related Interactions between Aflatoxin B1 and Tiamulin in Broiler Chickens

Sun,

Lootens,

Kabeta

et al. 2024

Toxins

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“…Pleuromutilin and its derivatives such as valnemulin, tiamulin, azamulin, and retapamulin have also shown significant antibacterial agents against MRSA. The probable mechanism might be the inhibition of protein synthesis by binding with peptidyl transferase constituents of 50S-subunit of ribosomes of bacteria [35]. Phloroglucinol and its acylphloroglucinol derivatives have shown promising anti-MRSA action.…”

Section: Natural Productsmentioning

confidence: 99%

Current Treatment Strategies Against Multidrug-Resistant Bacteria: A Review

et al. 2022

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There are several bacteria called superbugs that are resistant to multiple antibiotics which can be life threatening specially for critically ill and hospitalized patients. This article provides up-to-date treatment strategies employed against some major superbugs, like methicillin-resistant Staphylococcus aureus, carbapenem-resistant Enterobacteriaceae, vancomycin-resistant Enterococcus, multidrug-resistant Pseudomonas aeruginosa, and multidrug-resistant Escherichia coli. The pathogen-directed therapeutics decrease the toxicity of bacteria by altering their virulence factors by specific processes. On the other hand, the host-directed therapeutics limits these superbugs by modulating immune cells, enhancing host cell functions, and modifying disease pathology. Several new antibiotics against the global priority superbugs are coming to the market or are in the clinical development phase. Medicinal plants possessing potent secondary metabolites can play a key role in the treatment against these superbugs. Nanotechnology has also emerged as a promising option for combatting them. There is urgent need to continuously figure out the best possible treatment strategy against these superbugs as resistance can also be developed against the new and upcoming antibiotics in future. Rational use of antibiotics and maintenance of proper hygiene must be practiced among patients.

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“…The natural product pleuromutilin ( 1 , Figure ), discovered in 1951, , is an attractive foundation for new antibiotics. This is emphasized by the more than 40 pleuromutilin medicinal chemistry and total synthesis articles published within the field over the last 5 years, with some reporting very potent activity and high clinical potential, − and in some cases also by employing novel and unique strategies. ,,,,,− …”

Section: Introductionmentioning

confidence: 99%

Hit-to-Lead Identification and Validation of a Triaromatic Pleuromutilin Antibiotic Candidate

Heidtmann,

Fejer,

Stærk

et al. 2024

J. Med. Chem.

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Herein, we report the hit-to-lead identification of a drug-like pleuromutilin conjugate 16, based on a triaromatic hit reported in 2020. The lead arose as the clear candidate from a hitoptimization campaign in which Gram-positive antibacterial activity, solubility, and P-gp affinity were optimized. Conjugate 16 was extensively evaluated for its in vitro ADMET performance which, apart from solubility, was overall on par with lefamulin. This evaluation included Caco-2 cell permeability, plasma protein binding, hERG inhibition, cytotoxicity, metabolism in microsomes and CYP3A4, resistance induction, and time-kill kinetics. Intravenous pharmacokinetics of 16 proved satisfactory in both mice and pigs; however, oral bioavailability was limited likely due to insufficient solubility. The in vivo efficacy was evaluated in mice, systemically infected with Staphylococcus aureus, where 16 showed rapid reduction in blood bacteriaemia. Through our comprehensive studies, lead 16 has emerged as a highly promising and safe antibiotic candidate for the treatment of Gram-positive bacterial infections.

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Discovery of Novel Pleuromutilin Derivatives as Potent Antibacterial Agents for the Treatment of MRSA Infection

Cited by 6 publications

References 41 publications

Exploration of Cytochrome P450-Related Interactions between Aflatoxin B1 and Tiamulin in Broiler Chickens

Exploration of Cytochrome P450-Related Interactions between Aflatoxin B1 and Tiamulin in Broiler Chickens

Current Treatment Strategies Against Multidrug-Resistant Bacteria: A Review

Hit-to-Lead Identification and Validation of a Triaromatic Pleuromutilin Antibiotic Candidate

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