Extensively Drug-Resistant Salmonella typhi XDR Infection at Rawalpindi Medical University and Allied Hospitals

Izhar, Kausar; Ahmed, Kiran; Rehan, Maryyam; Umar, Muhammad; Ikram, Nadeem; Akhter, Naeem

doi:10.37939/jrmc.v24i4.1493

Cited by 3 publications

(2 citation statements)

References 17 publications

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“…Local government and authorities are exerting efforts to monitor sanitation processes, diagnosis, and proper medication against typhoid fever . Currently, the treatment of choice for deadly superbugs is a third-generation Cephalosporin such as ceftriaxone/cefotaxime as prescribed in a WHO report published on December 27, 2018 …”

Section: Introductionmentioning

confidence: 99%

“…6 Currently, the treatment of choice for deadly superbugs is a third-generation Cephalosporin such as ceftriaxone/ T h i s c o n t e n t i s cefotaxime as prescribed in a WHO report published on December 27, 2018. 7 The most important class of drugs used for the treatment of bacterial infections is β-lactam antibiotics. 8,9 Continuous use of such inhibitors is jeopardized by the antimicrobial resistance mechanism mediated by β-lactamases.…”

Section: Introductionmentioning

confidence: 99%

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Non-β Lactam Inhibitors of the Serine β-Lactamase blaCTX-M15 in Drug-Resistant Salmonella typhi

Ahmad,

Parvaiz,

MacKerell

et al. 2023

J. Chem. Inf. Model.

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Antibiotic resistance by bacterial pathogens against widely used β-lactam drugs is a major concern to public health worldwide, resulting in high healthcare cost. The present study aimed to extend previous research by investigating the potential activity of reported compounds against the S. typhi β-lactamase protein. 74 compounds from computational screening reported in our previous study against β-lactamase CMY-10 were subjected to docking studies against blaCTX-M15. Site-Identification by Ligand Competitive Saturation (SILCS)-Monte Carlo (SILCS-MC) was applied to the top two ligands selected from molecular docking studies to predict and refine their conformations for binding conformations against blaCTX-M15. The SILCS-MC method predicted affinities of −8.6 and −10.7 kcal/mol for Top1 and Top2, respectively, indicating low micromolar binding to the blaCTX-M15 active site. MD simulations initiated from SILCS-MC docked orientations were carried out to better characterize the dynamics and stability of the complexes. Important interactions anchoring the ligand within the active site include pi−pi stacked, amide−pi, and pi−alkyl interactions. Simulations of the Top2− blaCTX-M15 complex exhibited stability associated with a wide range of hydrogen-bond and aromatic interactions between the protein and the ligand. Experimental β-lactamase (BL) activity assays showed that Top1 has 0.1 u/mg BL activity, and Top2 has a BL activity of 0.038 u/mg with a minimum inhibitory concentration of 1 mg/mL. The inhibitors proposed in this study are non-βlactam-based β-lactamase inhibitors that exhibit the potential to be used in combination with β-lactam antibiotics against multidrugresistant clinical isolates. Thus, Top1 and Top2 represent lead compounds that increase the efficacy of β-lactam antibiotics with a low dose concentration.

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Section: Introductionmentioning

confidence: 99%