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Novel antimicrobials targeting the primary Na+ pump inhibit growth and intracellular proliferation

Novel antimicrobials targeting the primary Na+ pump inhibit growth and intracellular proliferation of Legionella pneumophila

Ryan Ramjiawan

University of Manitoba Max Rady College of Medicine

Introduction: Legionella pneumophila is the etiological agent accountable for Legionnaire’s disease. During infection, L. pneumophila is engulfed by the host alveolar macrophages via phagocytosis and confined within a vacuole. L. pneumophila has become progressively more resistant to many current antibiotics. The purpose of the present study was to determine if a novel, rationally designed, synthetic furanone compound named PEG-2S and its derivatives are potent inhibitors of Na+-NQR and if they are able to suppress the growth and viability of L. pneumophila bacteria, an Na+-NQR containing bacteria. Methods: To determine if the enzymatic activity of Na+-NQR could be directly inhibited by PEG-2S and its derivatives, sub-bacterial membrane vesicles from V. cholerae overexpressing Na+- NQR were isolated in standardized fashion. Assays were conducted measuring the spectrophotometric absorption change as a result of dNADH oxidation, representing a measure of enzymatic (Na+-NQR) activity in the presences of various PEG analogs. The IC50 of each tested inhibitor was measured for comparison. To determine if PEG analogs could inhibit L. pneumophila bacterial viability and growth in liquid culture, the bacteria was grown in standard fashion and used to inoculate 96 well plates. The obtained cultures were supplemented with 1, 2.5 or 10 μmol/L of various PEG analogs (or pure DMSO controls) and then incubated at 37°C for 18hrs. OD 600 was measured to determine bacterial concentration. Hep-2 cells were infected with L. pneumophila and a repeat of the above procedure was performed. Results: A newly designed line of furanone Na+-NQR inhibitors, PEG-2S and six of its derivatives, inhibited proliferation of L. pneumophila in liquid culture. The secondary amine PEG-6(Boc) also arrested growth of L. pneumophila in infected human (Hep 2) cells. Additionally, give of the PEG analogs were found to inhibit NADH oxidation in vesicles overexpressing the Na+-NQR enzyme with a half-minimal inhibitory concentration in the nanomolar range, illustrating the potency of these inhibitors. Conclusions: Na+-NQR in L. pneumophila is susceptible to PEG-type inhibitors. In the era of bacterial resistance, these are encouraging results along the path to developing novel antimicrobials with a unique target. This may aid in the ongoing effort to reduce the risk of transmission and spread of L. pneumophila and other Na+-NQR containing pathogens.

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