On the action of 5-amino-salicylic acid and sulfapyridine on M. avium including subspecies paratuberculosis.
BACKGROUND
Introduced in 1942, sulfasalazine (a conjugate of 5-aminosalicylic acid (5-ASA) and sulfapyridine) is the most prescribed medication used to treat "inflammatory" bowel disease (IBD.) Although controversial, there are increasingly compelling data that Mycobacterium avium subspecies paratuberculosis (MAP) may be an etiological agent in some or all of IBD. We have shown that two other agents used in the therapy of IBD (methotrexate and 6-MP) profoundly inhibit MAP growth. We concluded that their most plausible mechanism of action is as antiMAP antibiotics. We herein hypothesize that the mechanism of action of 5-ASA and/or sulfapyridine may also simply be to inhibit MAP growth.


METHODS
The effect on MAP growth kinetics by sulfasalazine and its components were evaluated in bacterial culture of two strains each of MAP and M. avium, using a radiometric ((14)CO(2) BACTEC(R)) detection system that quantifies mycobacterial growth as arbitrary "growth index units" (GI). Efficacy data are presented as "percent decrease in cumulative GI" (%-DeltacGI).


RESULTS
There are disparate responses to 5-ASA and sulfapyridine in the two subspecies. Against MAP, 5-ASA is inhibitory in a dose-dependent manner (MAP ATCC 19698 46%-DeltacGI at 64 microg/ml), whereas sulfapyridine has virtually no effect. In contrast, against M. avium ATCC 25291, 5-ASA has no effect, whereas sulfapyridine (88%-DeltacGI at 4 microg/ml) is as effective as methotrexate, our positive control (88%-DeltacGI at 4 microg/ml).


CONCLUSIONS
5-ASA inhibits MAP growth in culture. We posit that, unknowingly, the medical profession has been treating MAP infections since sulfasalazine's introduction in 1942. These observations may explain, in part, why MAP has not previously been identified as a human pathogen. We conclude that henceforth in clinical trials evaluating antiMAP agents in IBD, if considered ethical, the use of 5-ASA (as well as methotrexate and 6-MP) should be excluded from control groups.
Greenstein
Robert J
RJ
Departments of Surgery and Laboratory of Molecular Surgical Research, VA Medical Center, Bronx, New York, United States of America. BGAxis@aol.com
Su
Liya
L
Shahidi
Azra
A
Brown
Sheldon T
ST
D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002417:Cattle; D004359:Drug Therapy, Combination; D006801:Humans; D019804:Mesalamine / Q000494:pharmacology*; D016927:Mycobacterium avium subsp. paratuberculosis / Q000187:drug effects* / Q000254:growth & development / Q000472:pathogenicity; D010283:Paratuberculosis / Q000188:drug therapy* / Q000473:pathology; D013427:Sulfapyridine / Q000494:pharmacology*
D000890:Anti-Infective Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D019804:Mesalamine; D013427:Sulfapyridine