Computer-aided screening for potential inhibitory compounds against a Klebsiella pneumoniae local isolate containing SHV-1 and CTX-M antibiotic resistance genes

• Main Authors: Castro, Anna, Sy, Jamie Bernadette, Macalino, Stephani Joy Y., Morales, Nadia, Abid, Princess Alyssa, Billones, Junie, Carrillo, Maria Constancia
• Format: text
• Published: Animo Repository 2021
• Subjects: Klebsiella pneumoniae; Anti-infective agents; Medicinal-Pharmaceutical Chemistry
• Online Access: https://animorepository.dlsu.edu.ph/faculty_research/11454
• Institution: De La Salle University

Extended-spectrum beta-lactamases (ESBLs) allow bacteria to become resistant to commonly used antibiotics especially in common pathogens such as Klebsiella pneumoniae. ESBLs are a significant public health concern as their presence severely limits treatment options. Discovery and development of new drug entities are critical to effectively combat infections with these increasingly common antibiotic-resistant variants. Computational approaches can accelerate and reduce the cost of the discovery phase by screening for inhibitors of “druggable” pathogen enzyme targets in silico. In this study, the protein structures of the ESBL enzymes SHV-1 and CTX-M-15 were used as targets in molecular docking experiments to identify potential inhibitors. Twenty-six (26) compounds from the Enamine compound database were identified to have more favorable interactions compared to Avibactam, a known inhibitor of the target proteins. Their cytotoxic activities were tested in vivo using Resazurin Microtiter Assay (REMA) against a clinical isolate containing both SHV-1 and CTX-M-15 resistance genes. However, despite favorable binding energies in the in silico screening, most of the compounds exhibited negligible inhibition on the growth of Klebsiella pneumoniae in the in vitro assay. This may be attributed to the fact that a phenotypic whole-cell assay, instead of an enzyme-targeted assay, was used for validation. Cell permeability requires a different set of molecular parameters which were not part of the study. Doxorubicin exhibited the highest in vitro bactericidal activity against this strain, which agrees with its known activity against many other bacterial pathogens and may be a promising compound for further lead optimization.