New Role for FDA-Approved Drugs in Combating Antibiotic-Resistant Bacteria

Abstract

h Antibiotic resistance in medically relevant bacterial pathogens, coupled with a paucity of novel antimicrobial discoveries, represents a pressing global crisis. Traditional drug discovery is an inefficient and costly process; however, systematic screening of Food and Drug Administration (FDA)-approved therapeutics for other indications in humans offers a rapid alternative approach. In this study, we screened a library of 780 FDA-approved drugs to identify molecules that rendered RAW 264.7 murine macrophages resistant to cytotoxicity induced by the highly virulent Yersinia pestis CO92 strain. Of these compounds, we identified 94 not classified as antibiotics as being effective at preventing Y. pestis-induced cytotoxicity. A total of 17 prioritized drugs, based on efficacy in in vitro screens, were chosen for further evaluation in a murine model of pneumonic plague to delineate if in vitro efficacy could be translated in vivo. Three drugs, doxapram (DXP), amoxapine (AXPN), and trifluoperazine (TFP), increased animal survivability despite not exhibiting any direct bacteriostatic or bactericidal effect on Y. pestis and having no modulating effect on crucial Y. pestis virulence factors. These findings suggested that DXP, AXPN, and TFP may modulate host cell pathways necessary for disease pathogenesis. Finally, to further assess the broad applicability of drugs identified from in vitro screens, the therapeutic potential of TFP, the most efficacious drug in vivo, was evaluated in murine models of Salmonella enterica serovar Typhimurium and Clostridium difficile infections. In both models, TFP treatment resulted in increased survivability of infected animals. Taken together, these results demonstrate the broad applicability and potential use of nonantibiotic FDA-approved drugs to combat respiratory and gastrointestinal bacterial pathogens.

A Dormant Microbial Component in the Development of Preeclampsia

“…These must take care to avoid any Jarisch–Herxheimer reaction (1140–1143) due to the release from microbes induced by antibiotics of inflammagens such as LPS (1144–1147). A related strategy recognizes that some FDA-approved drugs can actually exert powerful antibiotic effects in vivo (but not on petri plates) by modifying the host (1148). …”

New Insights into Autoinducer-2 Signaling as a Virulence Regulator in a Mouse Model of Pneumonic Plague

“…Intracellular survival of Y. pestis strains was determined as previously described (40). In brief, luminescent Y. pestis strains were grown in HIB overnight to saturation at 28°C.…”

“…Western blotting for Y. pestis -secreted T3SS effectors was performed as previously described (40). In brief, overnight cultures of Y. pestis CO92 or its mutants, grown in HIB at 28°C, were diluted 1:20 in 5 ml HIB supplemented with 5 mM EGTA to trigger the low-calcium response.…”

“…Pla protease activity measurement was performed as previously described (40). In brief, bacteria were grown as described above for AI-2 analysis and collected at the time of maximal AI-2 level.…”

Evaluation of antimicrobial effect due to the results of in vitro photodynamic reaction modelling

“…Вопрос преодоления устойчивости микро-организмов к антибактериальным препаратам оста-ется актуальным и значимым в медицине. В настоя-щее время предложено множество способов лечения гнойно-воспалительных заболеваний мягких тканей, альтернативных антибактериальной терапии [1][2][3]. Одним из перспективных является аппликационный метод фотодинамической терапии [4][5][6][7][8].…”