Czyz D.M.,Argonne National Laboratory |
Czyz D.M.,University of Chicago |
Potluri L.-P.,Argonne National Laboratory |
Potluri L.-P.,University of Chicago |
And 15 more authors.
mBio | Year: 2014
We sought a new approach to treating infections by intracellular bacteria, namely, by altering host cell functions that support their growth. We screened a library of 640 Food and Drug Administration (FDA)-approved compounds for agents that render THP-1 cells resistant to infection by four intracellular pathogens. We identified numerous drugs that are not antibiotics but were highly effective in inhibiting intracellular bacterial growth with limited toxicity to host cells. These compounds are likely to target three kinds of host functions: (i) G protein-coupled receptors, (ii) intracellular calcium signals, and (iii) membrane cholesterol distribution. The compounds that targeted G protein receptor signaling and calcium fluxes broadly inhibited Coxiella burnetii, Legionella pneumophila, Brucella abortus, and Rickettsia conorii, while those directed against cholesterol traffic strongly attenuated the intracellular growth of C. burnetii and L. pneumophila. These pathways probably support intracellular pathogen growth so that drugs that perturb them may be therapeutic candidates. Combining host-and pathogendirected treatments is a strategy to decrease the emergence of drug-resistant intracellular bacterial pathogens.IMPORTANCE Although antibiotic treatment is often successful, it is becoming clear that alternatives to conventional pathogendirected therapy must be developed in the face of increasing antibiotic resistance. Moreover, the costs and timing associated with the development of novel antimicrobials make repurposed FDA-approved drugs attractive host-targeted therapeutics. This paper describes a novel approach of identifying such host-targeted therapeutics against intracellular bacterial pathogens. We identified several FDA-approved drugs that inhibit the growth of intracellular bacteria, thereby implicating host intracellular pathways presumably utilized by bacteria during infection. © 2014 Czyż et al.
Mathers A.,Vector borne Disease Laboratory |
Mathers A.,University of Virginia |
Mathers A.,Maine Medical Center Research Institute |
Smith R.P.,Vector borne Disease Laboratory |
And 15 more authors.
Journal of Vector Ecology | Year: 2011
The role of migratory birds in the dispersal of Ixodes scapularis ticks in the northeastern U.S. is well established and is presumed to be a major factor in the expansion of the geographic risk for Lyme disease. Population genetic studies of B. burgdorferi sensu stricto, the agent of Lyme disease in this region, consistently reveal the local presence of as many as 15 distinct strain types as designated by major groups of the ospC surface lipoprotein. Recent evidence suggests such strain diversity is adaptive to the diverse vertebrate hosts that maintain enzootic infection. How this strain diversity is established in emergent areas is unknown. To determine whether similar strain diversity is present in ticks imported by birds, we examined B. burgdorferi strains in I. scapularis ticks removed from migrants at an isolated island site. Tick mid-guts were cultured and isolates underwent DNA amplification with primers targeting ospC. Amplicons were separated by gel electrophoresis and sequenced. One hundred thirty-seven nymphal ticks obtained from 68 birds resulted in 24 isolates of B. burgdorferi representing eight ospC major groups. Bird-derived ticks contain diverse strain types of B. burgdorferi, including strain types associated with invasive Lyme disease. Birds and the ticks that feed on them may introduce a diversity of strains of the agent of Lyme disease to emergent areas. © 2011 The Society for Vector Ecology.