Evaluation of Nucleoside Analogs as Antimicrobials Targeting Unique Enzymes in Borrelia burgdorferi
PATHOGENS
Authors: Chakraborti, Monideep; Schlachter, Samantha; Primus, Shekerah; Wagner, Julie; Sweet, Brandi; Carr, Zoey; Cornell, Kenneth A.; Parveen, Nikhat
Abstract
The first line therapy for Lyme disease is treatment with doxycycline, amoxicillin, or cefuroxime. In endemic regions, the persistence of symptoms in many patients after completion of antibiotic treatment remains a major healthcare concern. The causative agent of Lyme disease is a spirochete,Borrelia burgdorferi, an extreme auxotroph that cannot exist under free-living conditions and depends upon the tick vector and mammalian hosts to fulfill its nutritional needs. Despite lacking all major biosynthetic pathways,B. burgdorferiuniquely possesses three homologous and functional methylthioadenosine/S-adenosylhomocysteine nucleosidases (MTANs: Bgp, MtnN, and Pfs) involved in methionine and purine salvage, underscoring the critical role these enzymes play in the life cycle of the spirochete. At least one MTAN, Bgp, is exceptional in its presence on the surface of Lyme spirochetes and its dual functionality in nutrient salvage and glycosaminoglycan binding involved in host-cell adherence. Thus, MTANs offer highly promising targets for discovery of new antimicrobials. Here we report on our studies to evaluate five nucleoside analogs for MTAN inhibitory activity, and cytotoxic or cytostatic effects on a bioluminescently engineered strain ofB. burgdorferi. All five compounds were either alternate substrates and/or inhibitors of MTAN activity, and reducedB. burgdorferigrowth. Two inhibitors: 5 '-deoxy-5 '-iodoadenosine (IADO) and 5 '-deoxy-5 '-ethyl-immucillin A (dEt-ImmA) showed bactericidal activity. Thus, these inhibitors exhibit high promise and form the foundation for development of novel and effective antimicrobials to treat Lyme disease.
Urban rodent reservoirs of Borrelia spp. in Warsaw, Poland
EPIDEMIOLOGY AND INFECTION
Authors: Gryczynska, A.; Gortat, T.; Kowalec, M.
Abstract
The anticipated worldwide surge in urban environments is generating ever-greater interest in the study of host-pathogen interactions in this specific type of habitat. We investigated the potential of city-inhabiting rodents to serve as the main Lyme borreliosis agents (Borrelia spp.) reservoir. We also tried to verify if anthropogenic disturbances changing the vertebrate species community composition may also alter the scheme of Borrelia spp. circulation. A total of 252 Apodemus mice (A. agrarius, A. flavicollis, A. sylvaticus) were captured in Warsaw (Poland), at sites classified into different zones of anthropogenic disturbance, ranging from suburban forests to municipal parks strictly in the city centre. Borrelia spp. infection, ascertained based on bacterium DNA presence in the rodents' blood, was found only in A. agrarius and A. flavicollis (7.6 and 6%, respectively). Only one species from the Borrelia genus - the mammal-associated species B. afzelii - was found in the mice studied. We found no statistical evidence of a correlation between infection in Apodemus mice and the zone of anthropogenic disturbance where the mice were caught. Non-homogeneous concentrations of Borelia spp. infected specimens within the strict city centre area suggest a lack of contact between members of particular mice subpopulations, and their responsibility for relatively high, but local Borrelia spp. infection.