In a bid to discovering novel antibiotics to combat growing trend of multi-drug resistance strains of Salmonella typhi, 48 new pyridine derivatives with significant inhibitory activities against the aforementioned bacterium were subjected to molecular docking against DNA gyrase protease of the bacterium, drug likeness evaluation and pharmacokinetics profiling. All the 48 leads displayed better binding affinity values when compared with Amoxicillin, Ciprofloxacin, Ceftriaxone, Ampicillin, and chloramphenicol, the standard antibiotics used herein for quality assurance. Furthermore, the majority of the compounds were, however, screened out due to their poor pharmacokinetics profiles and drug-likeness. Only five compounds emerged as the most promising leads and they include C4 with binding affinity of -8.0 kcal/mol, C8 (-8.6 kcal/mol), C9 (-8.1 kcal/mol), C26 (-8.3 kcal/mol), and C27 (-8.0 kcal/mol). These compounds not only displayed better binding affinity when compared with the reference antibiotics but also exhibit different modes of interactions with the target protease of the bacterium making them more potent and drug like. Toxicity evaluation of the leads also revealed that the compounds are neither tumorigenic nor mutagenic. In view of the excellent binding affinity, high pharmacokinetics profile and positive drug-likeness of the novel ligands, we recommend these promising compounds for in vitro and in vivo studies in order to discover novel antibiotics that could curb the dangerous trend of multiple drug resistance by Salmonella typhi.