In vivo activity of thiophene-containing trisubstituted methanes against acute and persistent infection of non-tubercular Mycobacterium fortuitum in a murine infection model.
OBJECTIVE
Mycobacterium fortuitum causes opportunist non-tubercular infection in humans. Chronic infection of M. fortuitum has been clinically documented and requires prolonged chemotherapy. The objectives of this study were to characterize acute and persistent infection of M. fortuitum in a murine infection model and to screen thiophene-containing trisubstituted methanes active against both acute and persistent infection.


METHODS
A murine infection model of M. fortuitum was used. Bacillary count, bioluminescence, disease symptoms, host immune response, drug susceptibility and mortality were measured. Reactivation of persistent bacilli was induced by dexamethasone. Trisubstituted methanes containing thiophene rings were synthesized and screened in vitro by agar dilution and BACTEC assay and in mice. Cytotoxicity was tested with Vero monkey kidney cells using a resazurin assay.


RESULTS
The acute infection in mice was marked by a 3 log rise in viable counts, the appearance of disease symptoms and a rise in the Th1 immune response. Bacilli were susceptible to fluoroquinolones. This was followed by persistent infection, in which disappearance of disease symptoms, a decline in Th1 response and non-susceptibility to fluoroquinolones was observed. When the mice were immunocompromised on day 40 post-infection (persistent state) by dexamethasone, a rise in viable counts, symptoms and susceptibility to fluoroquinolones and a prominent Th1 response reappeared. Two lead compounds were found that cleared the mice of bacilli in acute infection and caused a 2.29-2.99 log reduction in cfu of persistent bacilli.


CONCLUSIONS
The study established acute and persistent infection in mice and identified two promising anti-M. fortuitum compounds with a selectivity index >10.
Microbiology Division,  Central Drug Research Institute, CSIR, Lucknow 226001,  India.
Vivek Kr
VK
Kashyap
Ravi Kr
RK
Gupta
Rahul
R
Shrivastava
Brahm S
BS
Srivastava
Ranjana
R
Srivastava
Maloy Kumar
MK
Parai
Priyanka
P
Singh
Saurav
S
Bera
Gautam
G
Panda
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D005260:Female; D008697:Methane / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000633:toxicity; D051379:Mice; D008807:Mice, Inbred BALB C; D009164:Mycobacterium Infections / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D019907:Mycobacterium fortuitum / Q000187:drug effects*; D016019:Survival Analysis; D013876:Thiophenes / Q000008:administration & dosage* / Q000633:toxicity; D016896:Treatment Outcome; D014709:Vero Cells
D000900:Anti-Bacterial Agents; D013876:Thiophenes; D008697:Methane