Validated Preclinical Mouse Model for Therapeutic Testing against Multidrug-Resistant Pseudomonas aeruginosa Strains

Warawa, Jonathan M.; Duan, Xiaojiang; Anderson, Charles D.; Sotsky, Julie; Cramer, Daniel E.; Pfeffer, Tia L.; Guo, Haixun; Adcock, Scott; Lepak, Alexander J.; Andes, David R.; Slone, Stacey; Stromberg, Arnold J.; Gabbard, Jon D.; Severson, William; Lawrenz, Matthew B.

doi:10.1128/spectrum.02693-22

Cited by 5 publications

(4 citation statements)

References 21 publications

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“…Nowadays, resistance to β-lactams in S.aureus-mediated infections is a serious healthcare concern . The prevalence of antibiotic resistance among pathogens is a growing problem that draws attention to the development of new antibiotics . However, β-lactam antibiotics cause medication error that has been recognized as a common and serious threat to patient safety .…”

Section: Discussionmentioning

confidence: 99%

“… 36 The prevalence of antibiotic resistance among pathogens is a growing problem that draws attention to the development of new antibiotics. 37 However, β-lactam antibiotics cause medication error that has been recognized as a common and serious threat to patient safety. 38 β-Lactam antibiotics are found to be involved with severe adverse effects.…”

Section: Discussionmentioning

confidence: 99%

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Targeting Staphylococcal Cell–Wall Biosynthesis Protein FemX Through Steered Molecular Dynamics and Drug-Repurposing Approach

et al. 2023

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Staphylococcus aureus-mediated infection is a serious threat in this antimicrobial-resistant world. S. aureus has become a “superbug” by challenging conventional as well as modern treatment strategies. Nowadays, drug repurposing has become a new trend for the discovery of new drug molecules. This study focuses on evaluating FDA-approved drugs that can be repurposed against S. aureus infection. Steered molecular dynamics (SMD) has been performed for Lumacaftor and Olaparib against staphylococcal FemX to understand their binding to the active site. A time-dependent external force or rupture force has been applied to the ligands to calculate the force required to dislocate the ligand from the binding pocket. SMD analysis indicates that Lumacaftor has a high affinity for the substrate binding pocket in comparison to Olaparib. Umbrella sampling exhibits that Lumacaftor possesses a higher free energy barrier to displace it from the ligand-binding site. The bactericidal activity of Lumacaftor and Olaparib has been tested, and it shows that Lumacaftor has moderate activity along with biofilm inhibition potential (MIC value with conc. 128 μg/mL). Pharmacokinetic and toxicology evaluations indicate that Lumacaftor has higher pharmacokinetic potential with lower toxicity. This is the first experimental report where staphylococcal FemX has been targeted for the discovery of new drugs. It is suggested that Lumacaftor may be a potential lead molecule against S. aureus.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Targeting Staphylococcal Cell–Wall Biosynthesis Protein FemX Through Steered Molecular Dynamics and Drug-Repurposing Approach

et al. 2023

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“…Nowadays, resistance to β-lactams in S.aureus-mediated infections is a serious healthcare concern 36 . The prevalence of antibiotic resistance among pathogens is a growing problem that draws attention to the development of new antibiotics 37 . However, β-lactam antibiotics cause medication error that has been recognized as a common and serious threat to patient safety 38 .…”

Section: Discussionmentioning

confidence: 99%

Targeting staphylococcal cell-wall biosynthesis protein FemX through steered molecular dynamics and drug-repurposing approach

Rahman

Nath

Mohan

et al. 2023

Preprint

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Staphylococcus aureus-mediated infection is a serious threat in this antimicrobial-resistant world. S. aureus has become a superbug by challenging conventional as well as modern treatment strategies. Nowadays, drug repurposing has become a new trend for the discovery of new drug molecules. This study focuses on evaluating FDA-approved drugs that can be repurposed against S. aureus infection. Steered molecular dynamics (SMD) has been performed for Lumacaftor and Olaparib against staphylococcal FemX to understand their binding to the active site. A time-dependent external force or rupture has been applied to the ligands to calculate the force required to dislocate the ligand from the binding pocket. SMD analysis indicates that Lumacaftor has a high affinity for the substrate binding pocket in comparison to Olaparib. Umbrella sampling exhibits that Lumacaftor possesses a higher free energy barrier to displace it from the ligand-binding site. The bactericidal activity of Lumacaftor and Olaparib has been tested, and it shows that Lumacaftor has shown moderate activity along with biofilm inhibition potential (MIC value with conc. 128 μg/mL). Pharmacokinetic and toxicology evaluations indicate that Lumacaftor has higher pharmacokinetic potential with lower toxicity. This is the first experimental report where staphylococcal FemX has been targeted for the discovery of new drugs. It is suggested that Lumacaftor may be a potential lead molecule against S. aureus.

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“…The occurrence and spread of oral diseases among giant pandas, as well as their general health, are closely related to the oral flora [ 2 ]. Enterococcus faecium may cause severe disease that can be challenging to treat because of antibiotic resistance [ 3 , 4 ]. However, few reports to date have focused on the oral flora of giant pandas, especially with respect to virulence and antibiotic resistance.…”

Section: Introductionmentioning

confidence: 99%

Virulence gene detection and antimicrobial resistance analysis of Enterococcus faecium in captive giant pandas (Ailuropoda melanoleuca) in China

Liu

Huang

et al. 2023

Acta Vet Scand

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Background The emergence of multidrug resistance among enterococci makes effective treatment of enterococcal infections more challenging. Giant pandas (Ailuropoda melanoleuca) are vulnerable to oral trauma and lesions as they feast on bamboo. Enterococci may contaminate such oral lesions and cause infection necessitating treatment with antibiotics. However, few studies have focused on the virulence and drug resistance of oral-derived enterococci, including Enterococcus faecium, in giant pandas. In this study, we analyzed the prevalence of 8 virulence genes and 14 drug resistance genes in E. faecium isolates isolated from saliva samples of giant pandas held in captivity in China and examined the antimicrobial drug susceptibility patterns of the E. faecium isolates. Results Twenty-eight isolates of E. faecium were successfully isolated from the saliva samples. Four virulence genes were detected, with the acm gene showing the highest prevalence (89%). The cylA, cpd, esp, and hyl genes were not detected. The isolated E. faecium isolates possessed strong resistance to a variety of drugs; however, they were sensitive to high concentrations of aminoglycosides. The resistance rates to vancomycin, linezolid, and nitrofurantoin were higher than those previously revealed by similar studies in China and other countries. Conclusions The findings of the present study indicate the drugs of choice for treatment of oral E. faecium infection in the giant panda.

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Validated Preclinical Mouse Model for Therapeutic Testing against Multidrug-Resistant Pseudomonas aeruginosa Strains

Abstract: The prevalence of antibiotic resistance among bacterial pathogens is a growing problem that necessitates the development of new antibiotics. Preclinical animal models are important tools to facilitate and speed the development of novel antimicrobials.

Cited by 5 publications

References 21 publications

Targeting Staphylococcal Cell–Wall Biosynthesis Protein FemX Through Steered Molecular Dynamics and Drug-Repurposing Approach

Targeting Staphylococcal Cell–Wall Biosynthesis Protein FemX Through Steered Molecular Dynamics and Drug-Repurposing Approach

Targeting staphylococcal cell-wall biosynthesis protein FemX through steered molecular dynamics and drug-repurposing approach

Virulence gene detection and antimicrobial resistance analysis of Enterococcus faecium in captive giant pandas (Ailuropoda melanoleuca) in China

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