posted on 2019-09-25, 03:03authored byNeetu Dayal, Clement Opoku-Temeng, Haroon Mohammad, Nader S. Abutaleb, Delmis Hernandez, Kenneth Ikenna Onyedibe, Modi Wang, Matthias Zeller, Mohamed N. Seleem, Herman O. Sintim
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.