ABSTRACT
Over the past two decades, traditional antimicrobial strategies have lost efficacy due to a rapid rise in antibiotic resistance and limited success in developing new antibiotics. Rather than relying on therapeutics solely targeting the bacterial pathogen, therapies are emerging that simultaneously focus on host responses. Here, we describe the most promising 'host-informed therapies' (HITs) in two categories: those that aid patients with fully functional immune systems, and those that aid patients with perturbed immune processes. Using Streptococcus pneumoniae, the leading cause of bacterial pneumonia, as a case study, we show HITs as an attractive option for supplementing infection management. However, to broaden their applicability and design new strategies, targeted research and clinical trials will be essential.
Subject(s)
Pneumonia, Pneumococcal , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Humans , Pneumonia, Pneumococcal/drug therapy , Streptococcus pneumoniaeABSTRACT
A successful scaffold-hopping approach gave a novel series of inhibitors of bacterial glutamate racemase (MurI). Early SAR studies of the 8-benzyl pteridine-6,7-diones led to compounds with micromolar enzyme potency and antibacterial activity.
Subject(s)
Amino Acid Isomerases/antagonists & inhibitors , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Gram-Positive Bacteria/enzymology , Pteridines/chemical synthesis , Pteridines/pharmacology , Anti-Bacterial Agents/chemistry , Combinatorial Chemistry Techniques , Gram-Positive Bacteria/drug effects , Microbial Sensitivity Tests , Molecular Structure , Pteridines/chemistry , Structure-Activity RelationshipABSTRACT
An early SAR study of a screening hit series has generated a series of 9-benzyl purines as inhibitors of bacterial glutamate racemase (MurI) with micromolar enzyme potency and improved physical properties. X-ray co-crystal EI structures were obtained.
Subject(s)
Amino Acid Isomerases/antagonists & inhibitors , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Gram-Positive Bacteria/enzymology , Purines/chemical synthesis , Purines/pharmacology , Anti-Bacterial Agents/chemistry , Combinatorial Chemistry Techniques , Crystallography, X-Ray , Enterococcus faecalis/drug effects , Enterococcus faecalis/genetics , Enterococcus faecium/drug effects , Enterococcus faecium/genetics , Gram-Positive Bacteria/genetics , Molecular Conformation , Molecular Structure , Purines/chemistry , Staphylococcus aureus/drug effects , Staphylococcus aureus/genetics , Structure-Activity RelationshipABSTRACT
Helicobacter pylori infects the gastric mucosa of almost half of the worlds population and infection is associated with several gastrointestinal diseases, ranging in severity from superficial and chronic gastritis to duodenal ulceration and gastric adenocarcinoma. Developing new therapeutics against a bacterium with such a unique niche has proven challenging, and the current therapy is complex and increase of bacterial resistance to current antimicrobials and treatment failure has identified a need for newer, more potent compounds. Access to the genomic sequence of several H. pylori isolates has allowed a more focused, target-specific approach to the development of new therapeutics.