Legionnaire's Disease Presenting With the Legionella Triad (Pneumonia, Rhabdomyolysis, and Renal Failure) and Cardiac Complications.

Legionella pneumonia is well-characterized as a cause of atypical, community-acquired pneumonia in susceptible individuals. In recent years, extrapulmonary manifestations, including an emerging triad of Legionella pneumonia, rhabdomyolysis, and renal failure, have been identified. Here we report a case of Legionnaire's disease that presented non-classically, with subclinical pneumonia and non-ST elevated myocardial infarction (NSTEMI). Although he received early treatment with antibiotics, he developed the Legionellatriad during admission. He had several episodes of cardiopulmonary decompensation during his hospital course, eventually ending in his passing. This case serves to highlight the importance of early identification and intervention in regard to extrapulmonary Legionella infection.

Rationalizing the generation of broad spectrum antibiotics with the addition of a positive charge.

Antibiotic resistance of Gram-negative bacteria is largely attributed to the low permeability of their outer membrane (OM). Recently, we disclosed the eNTRy rules, a key lesson of which is that the introduction of a primary amine enhances OM permeation in certain contexts. To understand the molecular basis for this finding, we perform an extensive set of molecular dynamics (MD) simulations and free energy calculations comparing the permeation of aminated and amine-free antibiotic derivatives through the most abundant OM porin of E. coli, OmpF. To improve sampling of conformationally flexible drugs in MD simulations, we developed a novel, Monte Carlo and graph theory based algorithm to probe more efficiently the rotational and translational degrees of freedom visited during the permeation of the antibiotic molecule through OmpF. The resulting pathways were then used for free-energy calculations, revealing a lower barrier against the permeation of the aminated compound, substantiating its greater OM permeability. Further analysis revealed that the amine facilitates permeation by enabling the antibiotic to align its dipole to the luminal electric field of the porin and form favorable electrostatic interactions with specific, highly-conserved charged residues. The importance of these interactions in permeation was further validated with experimental mutagenesis and whole cell accumulation assays. Overall, this study provides insights on the importance of the primary amine for antibiotic permeation into Gram-negative pathogens that could help the design of future antibiotics. We also offer a new computational approach for calculating free-energy of processes where relevant molecular conformations cannot be efficiently captured.