1. Rational design of balanced dual-targeting antibiotics with limited resistance
- Author
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Balint Kintses, Danijel Kikelj, Ferenc Bogár, Martina Durcik, Gábor Draskovits, Bálint Vásárhelyi, D Kata, Martin Welin, Janez Ilaš, Petra Szili, Žiga Skok, Raymond Kimbung, Lejla Daruka, Ákos Nyerges, Lucija Peterlin Mašič, Imre Földesi, Csaba Pál, Anamarija Zega, Tamás Révész, Nace Zidar, Tihomir Tomašič, and Dorota Focht more...
- Subjects
0301 basic medicine ,Staphylococcus ,Antibiotics ,medicine.disease_cause ,Pathology and Laboratory Medicine ,DNA gyrase ,antibiotics ,0302 clinical medicine ,Medical Conditions ,Antibiotiki ,Drug Resistance, Multiple, Bacterial ,Medicine and Health Sciences ,Enzyme Inhibitors ,Biology (General) ,udc:615.4 ,Skin ,biology ,Antimicrobials ,General Neuroscience ,Drugs ,Hep G2 Cells ,Hydrogen-Ion Concentration ,Staphylococcal Infections ,bacterial resistance ,3. Good health ,Anti-Bacterial Agents ,Bacterial Pathogens ,Infectious Diseases ,Medical Microbiology ,udc:615.4:54:615.33 ,Vancomycin-resistant Staphylococcus aureus ,MCF-7 Cells ,Methicillin-resistant Staphylococcus aureus ,Pathogens ,General Agricultural and Biological Sciences ,Research Article ,Skin Infections ,Staphylococcus aureus ,Topoisomerase IV ,medicine.drug_class ,QH301-705.5 ,bacterial targets ,Farmacevtska kemija ,Microbial Sensitivity Tests ,Dermatology ,Staphylococcal infections ,Microbiology ,Skin Diseases ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Minimum inhibitory concentration ,Antibiotic resistance ,Bacterial Proteins ,Microbial Control ,Toxicity Tests ,medicine ,Animals ,Humans ,Amino Acid Sequence ,ddc:610 ,Microbial Pathogens ,Pharmacology ,General Immunology and Microbiology ,Bacteria ,Rational design ,Organisms ,Biology and Life Sciences ,medicine.disease ,Disease Models, Animal ,030104 developmental biology ,Drug Design ,Antibiotic Resistance ,Mutation ,biology.protein ,farmacevtska kemija ,Antibacterials ,Antimicrobial Resistance ,Directed Molecular Evolution ,antibiotiki ,030217 neurology & neurosurgery - Abstract
Antibiotics that inhibit multiple bacterial targets offer a promising therapeutic strategy against resistance evolution, but developing such antibiotics is challenging. Here we demonstrate that a rational design of balanced multitargeting antibiotics is feasible by using a medicinal chemistry workflow. The resultant lead compounds, ULD1 and ULD2, belonging to a novel chemical class, almost equipotently inhibit bacterial DNA gyrase and topoisomerase IV complexes and interact with multiple evolutionary conserved amino acids in the ATP-binding pockets of their target proteins. ULD1 and ULD2 are excellently potent against a broad range of gram-positive bacteria. Notably, the efficacy of these compounds was tested against a broad panel of multidrug-resistant Staphylococcus aureus clinical strains. Antibiotics with clinical relevance against staphylococcal infections fail to inhibit a significant fraction of these isolates, whereas both ULD1 and ULD2 inhibit all of them (minimum inhibitory concentration [MIC] ≤1 μg/mL). Resistance mutations against these compounds are rare, have limited impact on compound susceptibility, and substantially reduce bacterial growth. Based on their efficacy and lack of toxicity demonstrated in murine infection models, these compounds could translate into new therapies against multidrug-resistant bacterial infections., This study designs novel antimicrobial compounds that inhibit multiple bacterial targets, making the spontaneous evolution of resistance extremely rare. These compounds inhibited the growth of all multidrug resistant Staphylococcus aureus (MRSA) isolates tested, while existing antibiotics remained largely ineffective. more...
- Published
- 2020
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