Insights into the Effects and Mechanism of Andrographolide-Mediated Recovery of Susceptibility of Methicillin-Resistant Staphylococcus aureus to β-Lactam Antibiotics

Ma, Qiang; Wang, Guilai; Li, Na; Wang, Xin; Kang, Xinyun; Mao, Yanni; Wang, Guiqin

doi:10.1128/spectrum.02978-22

Cited by 5 publications

(4 citation statements)

References 49 publications

(51 reference statements)

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“…Ampicillin-sodium (Amp-Na), which is used in this study as a positive control, is a member of the extended-spectrum β-lactam family. 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 .…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

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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“…Ampicillin-sodium, which is used in this study as a positive control, is a member of the extended-spectrum β-lactam family. 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 .…”

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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“…Currently, MRSA is resistant to nearly all BLAs, limiting treatment options [15]. A major BLA determinant of MRSA is the expression of the mecA gene, which encodes penicillin binding protein 2A (PBP2a) [16]. MRSA generates insensitive affinity for PBP2a, which enables its related resistance to BLAs [11].…”

Section: Introductionmentioning

confidence: 99%

Synergism with Shikimic Acid Restores β-Lactam Antibiotic Activity against Methicillin-Resistant Staphylococcus aureus

Hou,

Ye,

Wang

et al. 2024

Molecules

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Methicillin-resistant Staphylococcus aureus (MRSA) has evolved into a dangerous pathogen resistant to beta-lactam antibiotics (BLAs) and has become a worrisome superbug. In this study, a strategy in which shikimic acid (SA), which has anti-inflammatory and antibacterial activity, is combined with BLAs to restart BLA activity was proposed for MRSA treatment. The synergistic effects of oxacillin combined with SA against oxacillin resistance in vitro and in vivo were investigated. The excellent synergistic effect of the oxacillin and SA combination was confirmed by performing the checkerboard assay, time-killing assay, live/dead bacterial cell viability assay, and assessing protein leakage. SEM showed that the cells in the control group had a regular, smooth, and intact surface. In contrast, oxacillin and SA or the combination treatment group exhibited different degrees of surface collapse. q-PCR indicated that the combination treatment group significantly inhibited the expression of the mecA gene. In vivo, we showed that the combination treatment increased the survival rate and decreased the bacterial load in mice. These results suggest that the combination of oxacillin with SA is considered an effective treatment option for MRSA, and the combination of SA with oxacillin in the treatment of MRSA is a novel strategy.

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Insights into the Effects and Mechanism of Andrographolide-Mediated Recovery of Susceptibility of Methicillin-Resistant Staphylococcus aureus to β-Lactam Antibiotics

Cited by 5 publications

References 49 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

Synergism with Shikimic Acid Restores β-Lactam Antibiotic Activity against Methicillin-Resistant Staphylococcus aureus

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