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Published on: August 16, 2021
On the effect of thalidomide on Mycobacterium avium subspecies paratuberculosis in culture
Robert J Greenstein1, Liya Su, Sheldon T Brown
1VAMC Bronx NY (112), 130 West Kingsbridge Rd, Bronx, NY 10468, USA. BGAxis@aol.com
Background:
Without known mechanisms of action, thalidomide is used to treat a variety of non-malignant 'idiopathic' diseases. There is increasing concern that Mycobacterium avium subspecies paratuberculosis (MAP) may be zoonotic. Recently, methotrexate, azathioprine, 6-mercaptopurine (6-MP), 5-aminosalicylic acid (5-ASA), cyclosporine A, rapamycin, and tacrolimus have been shown to inhibit MAP growth in culture, indicating that, unknowingly, MAP infections may have been treated for decades. We herein test the hypothesis that thalidomide may inhibit MAP growth.
Methods:
Using the radiometric 14CO2 (Bactec) system we quantified growth kinetics of thalidomide (+/-), (+), and (-) and two components for thalidomide, phthalimide and 1-hydroxypiperidine-2,6-dione (HPD). We studied four MAP strains (three human isolates, 'Ben', 'Dominic', and UCF-4, and a bovine MAP isolate 19698) and three mycobacterial controls (Mycobacterium avium and bacillus Calmette-Guérin (BCG)). Growth was quantified as growth index (GI) and inhibition as percent decrease in cumulative GI (%-DeltacGI).
Results:
Phthalimide had no dose-dependent inhibition on any strain. Neither thalidomide nor HPD inhibited M. avium or BCG. MAP inhibition varied; at 64 microg/ml, amongst human isolates, Dominic was most susceptible: thalidomide (+)=58%-DeltacGI and HPD=46%-DeltacGI. UCF-4 was next: thalidomide (-)=37%-DeltacGI and HPD=40%-DeltacGI. Ben was least susceptible: HPD=24%-DeltacGI.
Conclusions:
We have shown, in culture, the heretofore-undescribed inhibition of MAP growth by thalidomide and its enantiomers. Phthalimide was found to have no anti-MAP activity, whereas HPD was found to inhibit MAP growth. These data are compatible with the hypothesis that thalidomide, like other 'anti-inflammatories' and 'immunomodulators' may act, in part, as an anti-MAP antibiotic.
Insights
Thalidomide and its component HPD inhibit Mycobacterium avium subspecies paratuberculosis (MAP) growth in culture. Phthalimide showed no anti-MAP activity, suggesting thalidomide may act as an antibiotic against MAP infections.
Area of Science:
- Microbiology
- Pharmacology
Background:
- Thalidomide treats idiopathic diseases with unknown mechanisms.
- Mycobacterium avium subspecies paratuberculosis (MAP) is a potential zoonotic pathogen.
- Several drugs, including methotrexate and 5-ASA, inhibit MAP growth in vitro.
Purpose of the Study:
- To test the hypothesis that thalidomide inhibits MAP growth.
- To investigate the anti-MAP activity of thalidomide and its components.
Main Methods:
- Radiometric 14CO2 (Bactec) system used to quantify MAP growth kinetics.
- Tested thalidomide (racemic, enantiomers) and its components (phthalimide, HPD).
- Evaluated four MAP strains and two control mycobacteria (M. avium, BCG).
Main Results:
- Phthalimide showed no dose-dependent inhibition of any mycobacterial strain.
- Thalidomide and HPD did not inhibit M. avium or BCG.
- MAP strains exhibited variable inhibition; human isolate 'Dominic' was most susceptible to thalidomide and HPD.
Conclusions:
- Thalidomide and its component HPD demonstrate previously undescribed inhibition of MAP growth in vitro.
- Phthalimide lacks anti-MAP activity, while HPD exhibits inhibitory effects.
- Findings support thalidomide's potential role as an anti-MAP antibiotic, alongside its immunomodulatory functions.
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