Limits...
Optimization and Evaluation of 5-Styryl-Oxathiazol-2-one Mycobacterium tuberculosis Proteasome Inhibitors as Potential Antitubercular Agents.

Russo F, Gising J, Åkerbladh L, Roos AK, Naworyta A, Mowbray SL, Sokolowski A, Henderson I, Alling T, Bailey MA, Files M, Parish T, Karlén A, Larhed M - ChemistryOpen (2015)

Bottom Line: As part of the study, the structure-activity relationship of oxathiazolones as Mtb proteasome inhibitors has been investigated.Furthermore, the prepared compounds displayed a good selectivity profile for Mtb compared to the human proteasome.The results suggest that this new class of Mtb proteasome inhibitors has the potential to be further developed into novel antitubercular agents for synergistic combination therapies with existing drugs.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, BMC, Uppsala University Box 574, 751 23, Uppsala, Sweden.

ABSTRACT
This is the first report of 5-styryl-oxathiazol-2-ones as inhibitors of the Mycobacterium tuberculosis (Mtb) proteasome. As part of the study, the structure-activity relationship of oxathiazolones as Mtb proteasome inhibitors has been investigated. Furthermore, the prepared compounds displayed a good selectivity profile for Mtb compared to the human proteasome. The 5-styryl-oxathiazol-2-one inhibitors identified showed little activity against replicating Mtb, but were rapidly bactericidal against nonreplicating bacteria. (E)-5-(4-Chlorostyryl)-1,3,4-oxathiazol-2-one) was most effective, reducing the colony-forming units (CFU)/mL below the detection limit in only seven days at all concentrations tested. The results suggest that this new class of Mtb proteasome inhibitors has the potential to be further developed into novel antitubercular agents for synergistic combination therapies with existing drugs.

No MeSH data available.


Related in: MedlinePlus

5-Styryl-oxathiazol-2-ones are bactericidal against nonreplicating Mycobacterium tuberculosis (Mtb). Mtb was grown aerobically, washed, and resuspended in PBS-tyloxapol for 14 d. Compounds were added with the indicated concentrations. Colony forming units (CFU) were determined by plating serial dilutions. The lower limit of detection (LoD) is indicated.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4522185&req=5

fig02: 5-Styryl-oxathiazol-2-ones are bactericidal against nonreplicating Mycobacterium tuberculosis (Mtb). Mtb was grown aerobically, washed, and resuspended in PBS-tyloxapol for 14 d. Compounds were added with the indicated concentrations. Colony forming units (CFU) were determined by plating serial dilutions. The lower limit of detection (LoD) is indicated.

Mentions: Previous work suggested that the proteasome plays a key role during oxidative and nitrosative stress,12 and that proteasome inhibitors are bactericidal against nonreplicating Mtb subjected to nitrosative stress.7c We therefore determined whether the 5-styryl-oxathiazolone class of compounds had activity against Mtb under nonreplicating conditions. For this we used a starvation model, in which bacteria are nutrientdeprived for 14 days,24 to induce the nonreplicating state, after which they are exposed to compounds over 21 days in this state (Figure 2).


Optimization and Evaluation of 5-Styryl-Oxathiazol-2-one Mycobacterium tuberculosis Proteasome Inhibitors as Potential Antitubercular Agents.

Russo F, Gising J, Åkerbladh L, Roos AK, Naworyta A, Mowbray SL, Sokolowski A, Henderson I, Alling T, Bailey MA, Files M, Parish T, Karlén A, Larhed M - ChemistryOpen (2015)

5-Styryl-oxathiazol-2-ones are bactericidal against nonreplicating Mycobacterium tuberculosis (Mtb). Mtb was grown aerobically, washed, and resuspended in PBS-tyloxapol for 14 d. Compounds were added with the indicated concentrations. Colony forming units (CFU) were determined by plating serial dilutions. The lower limit of detection (LoD) is indicated.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4522185&req=5

fig02: 5-Styryl-oxathiazol-2-ones are bactericidal against nonreplicating Mycobacterium tuberculosis (Mtb). Mtb was grown aerobically, washed, and resuspended in PBS-tyloxapol for 14 d. Compounds were added with the indicated concentrations. Colony forming units (CFU) were determined by plating serial dilutions. The lower limit of detection (LoD) is indicated.
Mentions: Previous work suggested that the proteasome plays a key role during oxidative and nitrosative stress,12 and that proteasome inhibitors are bactericidal against nonreplicating Mtb subjected to nitrosative stress.7c We therefore determined whether the 5-styryl-oxathiazolone class of compounds had activity against Mtb under nonreplicating conditions. For this we used a starvation model, in which bacteria are nutrientdeprived for 14 days,24 to induce the nonreplicating state, after which they are exposed to compounds over 21 days in this state (Figure 2).

Bottom Line: As part of the study, the structure-activity relationship of oxathiazolones as Mtb proteasome inhibitors has been investigated.Furthermore, the prepared compounds displayed a good selectivity profile for Mtb compared to the human proteasome.The results suggest that this new class of Mtb proteasome inhibitors has the potential to be further developed into novel antitubercular agents for synergistic combination therapies with existing drugs.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, BMC, Uppsala University Box 574, 751 23, Uppsala, Sweden.

ABSTRACT
This is the first report of 5-styryl-oxathiazol-2-ones as inhibitors of the Mycobacterium tuberculosis (Mtb) proteasome. As part of the study, the structure-activity relationship of oxathiazolones as Mtb proteasome inhibitors has been investigated. Furthermore, the prepared compounds displayed a good selectivity profile for Mtb compared to the human proteasome. The 5-styryl-oxathiazol-2-one inhibitors identified showed little activity against replicating Mtb, but were rapidly bactericidal against nonreplicating bacteria. (E)-5-(4-Chlorostyryl)-1,3,4-oxathiazol-2-one) was most effective, reducing the colony-forming units (CFU)/mL below the detection limit in only seven days at all concentrations tested. The results suggest that this new class of Mtb proteasome inhibitors has the potential to be further developed into novel antitubercular agents for synergistic combination therapies with existing drugs.

No MeSH data available.


Related in: MedlinePlus