Abstract
Background Mycobacterium avium subspecies paratuberculosis (MAP) may be zoonotic. Recently the “immuno-modulators” methotrexate, azathioprine and 6-MP and the “anti-inflammatory” 5-ASA have been shown to inhibit MAP growth in vitro. We concluded that their most plausible mechanism of action is as antiMAP antibiotics. The “immunosuppressants” Cyclosporine A, Rapamycin and Tacrolimus (FK 506) treat a variety of “autoimmune” and “inflammatory” diseases. Rapamycin and Tacrolimus are macrolides. We hypothesized that their mode of action may simply be to inhibit MAP growth.MethodologyThe effect on radiometric MAP 14CO2 growth kinetics of Cyclosporine A, Rapamycin and Tacrolimus on MAP cultured from humans (Dominic & UCF 4) or ruminants (ATCC 19698 & 303) and M. avium subspecies avium (ATCC 25291 & 101) are presented as “percent decrease in cumulative GI” (%-ΔcGI.)Principal FindingsThe positive control clofazimine has 99%-ΔcGI at 0.5 µg/ml (Dominic). Phthalimide, a negative control has no dose dependent inhibition on any strain. Against MAP there is dose dependent inhibition by the immunosuppressants. Cyclosporine has 97%-ΔcGI by 32 µg/ml (Dominic), Rapamycin has 74%-ΔcGI by 64 µg/ml (UCF 4) and Tacrolimus 43%-ΔcGI by 64 µg/ml (UCF 4)ConclusionsWe show heretofore-undescribed inhibition of MAP growth in vitro by “immunosuppressants;” the cyclic undecapeptide Cyclosporine A, and the macrolides Rapamycin and Tacrolimus. These data are compatible with our thesis that, unknowingly, the medical profession has been treating MAP infections since 1942 when 5-ASA and subsequently azathioprine, 6-MP and methotrexate were introduced in the therapy of some “autoimmune” and “inflammatory” diseases.
Highlights
The ‘‘immunosuppressants’’ Cyclosporine A [1], Rapamycin [2] and Tacrolimus (FK 506) [3] have conventionally been used to prevent or treat the rejection of transplanted organs.[4,5,6,7,8] They have well described mechanisms of actions [9,10] including calcineurin phosphatase inhibition by Cyclosporine and Tacrolimus and cell cycle inhibition by Rapamycin.[11]
We show heretofore-undescribed inhibition of Mycobacterium avium subspecies paratuberculosis (MAP) growth in vitro by ‘‘immunosuppressants;’’ the cyclic undecapeptide Cyclosporine A, and the macrolides Rapamycin and Tacrolimus
These data are compatible with our thesis that, unknowingly, the medical profession has been treating MAP infections since 1942 when 5 amino salicylic acid (5-ASA) and subsequently azathioprine, 6-MP and methotrexate were introduced in the therapy of some ‘‘autoimmune’’ and ‘‘inflammatory’’ diseases
Summary
The ‘‘immunosuppressants’’ Cyclosporine A [1], Rapamycin [2] and Tacrolimus (FK 506) [3] have conventionally been used to prevent or treat the rejection of transplanted organs.[4,5,6,7,8] They have well described mechanisms of actions [9,10] including calcineurin phosphatase inhibition by Cyclosporine and Tacrolimus and cell cycle inhibition by Rapamycin.[11]. It was unrecognized that the ‘‘anti-inflammatory’’ 5 amino salicylic acid (5-ASA) [37] and the ‘‘immune modulators’’ methotrexate [34], azathioprine [38] and its metabolite 6-mercapto-purine (6-MP) [34], [38] are antiMAP antibiotics. Antecedent studies evaluating the potential zoonotic character of MAP had permitted these ‘‘anti-inflammatory’’ and ‘‘immune-modulating’’ agents to be used in the control groups, as their antiMAP activity was not appreciated. The ‘‘immuno-modulators’’ methotrexate, azathioprine and 6-MP and the ‘‘anti-inflammatory’’ 5-ASA have been shown to inhibit MAP growth in vitro. We concluded that their most plausible mechanism of action is as antiMAP antibiotics. We hypothesized that their mode of action may be to inhibit MAP growth
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