Ceforanide

Following the invasion of eukaryotic cells, Salmonella enterica serovar Typhimurium replaces PBP2/PBP3, main targets of β-lactam antibiotics, with PBP2SAL/PBP3SAL, two homologue peptidoglycan synthases absent in Escherichia coli. PBP3SAL promotes pathogen cell division in acidic environments independently of PBP3 and shows low affinity for β-lactams that bind to PBP3 such as aztreonam, cefepime, cefotaxime, ceftazidime, ceftriaxone, cefuroxime and cefalotin.

To find compounds with high affinity for PBP3SAL to control Salmonella intracellular infections.

An S. Typhimurium ΔPBP3 mutant that divides using PBP3SAL and its parental wild-type strain, were exposed to a library of 1520 approved drugs in acidified (pH 4.6) nutrient-rich LB medium. Changes in optical density associated with cell filamentation, a read-out of blockage in cell division, were monitored. Compounds causing filamentation in the ΔPBP3 mutant but not in wild-type strain—the latter strain expressing both PBP3 and PBP3SAL in LB pH 4.6—were selected for further study. The bactericidal effect due to PBP3SAL inhibition was evaluated in vitro using a bacterial infection model of cultured fibroblasts.

The cephalosporin cefotiam exhibited higher affinity for PBP3SAL than for PBP3 in bacteria growing in acidified LB pH 4.6 medium. Cefotiam also proved to be effective against intracellular Salmonella in a PBP3SAL-dependent manner. Conversely, cefuroxime, which has higher affinity for PBP3, showed decreased effectiveness in killing intracellular Salmonella.

Antibiotics with affinity for PBP3SAL, like the cephalosporin cefotiam, have therapeutic value for treating Salmonella intracellular infections.

Salmonella is a widely distributed pathogen causing infection of intestinal tract, typhoid, and paratyphoid fever. Number of drugs was developed against salmonella, but in the last few decades due to the emergence of drug resistant strains, most of these drugs became dormant. As a result Salmonellosis emerges as a trivial cause of human mortality worldwide; therefore, there is an urgent need for unexploited drug targets and drugs to treat Salmonellosis. As development of new drug molecules is very time consuming and costly, drug repurposing is in consideration as a better alternative. With the aim to identify a new drug molecule against the Salmonella through repurposing approach, we utilized 14 well reported druggable targets known to play a vital role in the life cycle of pathogens. These targets were used to screen DrugBank and got 53 FDA approved drugs against them. To find the interaction between considered target proteins and screened drugs, molecular docking was performed. Fourteen docked drug-target complexes with reasonable binding affinities were subjected to Molecular Dynamics Simulation (MDS) at 150 ns, using Amber18. At the end MMPBSA and MMGBSA calculations were performed for all stable complexes and finally, got 3 precise and favourable complexes, i.e. ArcB-Cefpiramide, MrcB-Cefoperazone, and PhoQ-Carindacillin. Rigorous structural and energetic analysis for these complexes validates the potential of drug molecules to act as therapeutic drugs against Salmonella enterica. With this study we hypothesize that the drugs Cefpiramide (DB00430), Cefoperazone (DB01329) and Carindacillin (DB09319) will be the good repurposed-drugs for the treatment of Salmonellosis. Communicated by Ramaswamy H. Sarma.