With the ever-increasing problem of antibiotic resistance and the concurrent use of antibiotics in the food chain and in agriculture, there is an urgent and unmet need for new classes of antibiotics. Lantibiotics represent a large untapped pipeline of attractive scaffolds for the development of novel antibiotics. Previous in vitro and in vivo studies support the concept that lantibiotics are efficacious in Gram-positive models of infection, and that they are safe. Mutacin 1140 (MU1140) is a lantibiotic discovered by Oragenics, which has received considerable attention as a potentially novel antimicrobial agent because of its spectrum of activity, potency, low frequency of antimicrobial resistance, limited cytotoxicity, and overall pharmacological profile. MU1140 is an attractive scaffold for future antibiotic engineering by virtue of its excellent safety profile, novel Mechanism of Action, and the bacterias limited ability to develop resistance once it will be used in the clinic. In the proposed research, we will investigate in silico the interaction between MU1140 and its molecular target, to rank top performers of new analogs of MU1140 using molecular modeling. Those virtually screened compounds will be prioritized based on relevant pharmacologic properties. Lead compounds from computer modeling will be synthesized in the laboratory, purified, and characterized to confirm their solubility and stability in human serum, and that the substitution/modification did not negatively impact the potency of the analogs, as compared to MU1140. By the end of the proposed Phase 1 project, we will have confirmed the critical characteristics of synthetic analogs designed in silico, which will provide a solid framework for future development. This application is a joint effort between PI Park and Dr. Handfield at Oragenics, and their collaborators from Florida International University, Profs. Gerstman and Chapagain. Investigators will work closely together to implement the goals of the project and ensure the aims and tasks are performed in a timely manner. Public Health Relevance Statement NARRATIVE Lantibiotics represent a large untapped pipeline of attractive scaffolds for the development of novel antibiotics. Previous studies in vitro and in animals support the concept that lantibiotics are efficacious in Gram-positive models of infection, and that they are safe. Mutacin 1140 (MU1140) is a lantibiotic discovered by Oragenics, which has received considerable attention as a potential antimicrobial agent thanks to its unique properties and novel mechanism of action.
Project Terms: Affect ; Agriculture ; agricultural ; Algorithms ; Amines ; amine ; Amino Acids ; aminoacid ; Animals ; Antibiotics ; Antibiotic Agents ; Antibiotic Drugs ; Miscellaneous Antibiotic ; Attention ; Bacteria ; chemical synthesis ; Clinical Trials ; Computer Simulation ; Computer based Simulation ; computational simulation ; computerized simulation ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Engineering ; Fermentation ; Florida ; Future ; Goals ; Human ; Modern Man ; In Vitro ; Infection ; Joints ; Laboratories ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Libraries ; Lipids ; Nisin ; Peptides ; Drug Kinetics ; Pharmacokinetics ; Pharmacology ; Plasma ; Blood Plasma ; Plasma Serum ; Reticuloendothelial System, Serum, Plasma ; Publications ; Scientific Publication ; Diphosphates ; Pyrophosphates ; Research ; Research Personnel ; Investigators ; Researchers ; Risk ; Safety ; Solubility ; Testing ; Time ; Universities ; Water ; Hydrogen Oxide ; Work ; Hydroxyl Radical ; Hydroxyl ; lanthionine ; Antibiotic Resistance ; Resistance to antibiotics ; Resistant to antibiotics ; antibiotic drug resistance ; antibiotic resistant ; Computer-Aided Design ; Computer-Assisted Design ; base ; improved ; Solid ; Phase ; Biological ; Physiological ; Physiologic ; Ensure ; Chemicals ; Serum ; Blood Serum ; analog ; Collaborations ; Metabolic ; scaffolding ; scaffold ; anti-microbial agent ; anti-microbial drug ; antimicrobial agent ; antimicrobial drug ; Frequencies ; Complex ; Clinic ; Amino Acid Substitution ; Lytotoxicity ; cytotoxicity ; experience ; Food Chain ; membrane structure ; Membrane ; Molecular Dynamics Simulation ; molecular dynamics ; peptide analog ; functional group ; hydrophilicity ; Molecular Modeling Nucleic Acid Biochemistry ; Molecular Modeling Protein/Amino Acid Biochemistry ; Molecular Models ; molecular modeling ; Toxicities ; Toxic effect ; Structure ; simulation ; novel ; Position ; Positioning Attribute ; Modeling ; Property ; Molecular Computations ; Molecular Interaction ; Binding ; Effectiveness ; Address ; Antimicrobial resistant ; Resistance to antimicrobial ; anti-microbial resistance ; anti-microbial resistant ; resistance to anti-microbial ; resistant to anti-microbial ; resistant to antimicrobial ; Antimicrobial Resistance ; Data ; International ; Molecular Target ; in vivo ; Seminal ; Characteristics ; Molecular ; Process ; Docking ; Modification ; Derivation procedure ; Derivation ; Development ; developmental ; virtual ; design ; designing ; scale up ; Resistance development ; Resistant development ; developing resistance ; Resistance ; resistant ; drug candidate ; preservation ; lead candidate ; manufacturability ; Computer Models ; Computerized Models ; computational modeling ; computational models ; computer based models ; computerized modeling ; in silico ; virtual screening ; virtual screenings ;
