Inhibitors of Intracellular Gram-Positive Bacterial Growth Synthesized via Povarov–Doebner Reactions
- Neetu DayalNeetu DayalChemistry Department, Institute for Drug Discovery, Purdue University, 720 Clinic Drive, West Lafayette, Indiana 47907, United StatesMore by Neetu Dayal,
- Clement Opoku-TemengClement Opoku-TemengChemistry Department, Institute for Drug Discovery, Purdue University, 720 Clinic Drive, West Lafayette, Indiana 47907, United StatesChemistry and Biochemistry Department, University of Maryland, 8051 Regents Drive, College Park, Maryland 20742, United StatesMore by Clement Opoku-Temeng,
- Haroon MohammadHaroon MohammadDepartment of Comparative Pathobiology, Purdue University College of Veterinary Medicine, 625 Harrison Street, West Lafayette, Indiana 47907, United StatesMore by Haroon Mohammad,
- Nader S. AbutalebNader S. AbutalebDepartment of Comparative Pathobiology, Purdue University College of Veterinary Medicine, 625 Harrison Street, West Lafayette, Indiana 47907, United StatesMore by Nader S. Abutaleb,
- Delmis HernandezDelmis HernandezChemistry Department, Institute for Drug Discovery, Purdue University, 720 Clinic Drive, West Lafayette, Indiana 47907, United StatesMore by Delmis Hernandez,
- Kenneth Ikenna OnyedibeKenneth Ikenna OnyedibeChemistry Department, Institute for Drug Discovery, Purdue University, 720 Clinic Drive, West Lafayette, Indiana 47907, United StatesPurdue Institute of Inflammation, Immunology, and Infectious Disease, West Lafayette, Indiana 47907, United StatesMore by Kenneth Ikenna Onyedibe,
- Modi WangModi WangChemistry Department, Institute for Drug Discovery, Purdue University, 720 Clinic Drive, West Lafayette, Indiana 47907, United StatesMore by Modi Wang,
- Matthias ZellerMatthias ZellerChemistry Department, Institute for Drug Discovery, Purdue University, 720 Clinic Drive, West Lafayette, Indiana 47907, United StatesMore by Matthias Zeller,
- Mohamed N. SeleemMohamed N. SeleemDepartment of Comparative Pathobiology, Purdue University College of Veterinary Medicine, 625 Harrison Street, West Lafayette, Indiana 47907, United StatesPurdue Institute of Inflammation, Immunology, and Infectious Disease, West Lafayette, Indiana 47907, United StatesMore by Mohamed N. Seleem, and
- Herman O. Sintim*Herman O. Sintim*E-mail: [email protected]Chemistry Department, Institute for Drug Discovery, Purdue University, 720 Clinic Drive, West Lafayette, Indiana 47907, United StatesPurdue Institute of Inflammation, Immunology, and Infectious Disease, West Lafayette, Indiana 47907, United StatesMore by Herman O. Sintim
Abstract
Staphylococcus aureus can survive both inside and outside of phagocytic and nonphagocytic host cells. Once in the intracellular milieu, most antibiotics have reduced ability to kill S. aureus, thus resulting in relapse of infection. Consequently, there is a need for antibacterial agents that can accumulate to lethal concentrations within host cells to clear intracellular infections. We have identified tetrahydrobenzo[a or c]phenanthridine and tetrahydrobenzo[a or c]acridine compounds, synthesized via a one-flask Povarov–Doebner operation from readily available amines, aldehydes, and cyclic ketones, as potent agents against drug-resistant S. aureus. Importantly, the tetrahydrobenzo[a or c]phenanthridine and tetrahydrobenzo[a or c]acridine compounds can accumulate in macrophage cells and reduce the burden of intracellular MRSA better than the drug of choice, vancomycin. We observed that MRSA could not develop resistance (by passage 30) against tetrahydrobenzo[a or c]acridine compound 15. Moreover, tetrahydrobenzo[c]acridine compound 15 and tetrahydrobenzo[c]phenanthridine compound 16 were nontoxic to red blood cells and were nonmutagenic. Preliminary data indicated that compound 16 reduced bacterial load (MRSA USA300) in mice (thigh infection model) to the same degree as vancomycin. These observations suggest that compounds 15 and 16 and analogues thereof could become therapeutic agents for the treatment of chronic MRSA infections.
Cited By
This article is cited by 1 publications.
- Haroon Mohammad, Nader S. Abutaleb, Mohamed N. Seleem. Auranofin Rapidly Eradicates Methicillin-resistant Staphylococcus aureus (MRSA) in an Infected Pressure Ulcer Mouse Model. Scientific Reports 2020, 10 (1) https://doi.org/10.1038/s41598-020-64352-2