Obstructing 's virulence in eukaryotic cells through design of its SipB protein antagonists.

Objective: Typhoid fever, a disease caused by , is a leading cause of morbidity and mortality, particularly in developing nations. The evolution of resistance mechanisms to existing antibiotics has necessitated a search for newer drug candidates. This study used computer aided drug design techniques to design novel antibiotics that function by antagonizing SipB, an effector protein of the bacterium that is responsible for its pathogenicity and virulence in eukaryotic host cells.

Methods: A data set of 32 bioactive molecules with established antibacterial activity against was retrieved from the PubChem data base; optimized through a DFT approach in Spartan 14 software; and further subjected to QSAR modeling in BIOVIA-Accelrys Material Studio. The validated model (R = 0.80, R  = 0.78, Q  = 0.74, R  = 0.54, lack of fit = 0.07) revealed the dominant influence of MATS6c and E3p descriptors on the observed antibacterial activity of the compounds. Information from the model was used to optimize the structures of selected lead compounds in the data set, thus leading to the design of a highly potent set of novel analogues denoted D-1, D-2 and D-3.

Results: The predicted MIC values of D-1, D-2 and D-3 were 1.03, 0.73 and 0.30 μg/mL, respectively. Furthermore, molecular docking studies on these novel ligands against the active sites of SipB revealed binding energy values of -8.0, -7.7 and -7.7 kcal/mol for D-1, D-2 and D-3, respectively. These values were better than the -7.0 kcal/mol recorded for ciprofloxacin, the reference antibiotic used herein for quality assurance. In addition, drug-likeness and ADMET evaluation of the designed compounds revealed that they are orally bioavailable and exhibit excellent pharmacokinetic and toxicological profiles.

Conclusion: The current findings may provide a roadmap for the discovery of more potent antibiotics against