Journal
BIOCHEMISTRY
Volume 46, Issue 43, Pages 11998-12004Publisher
AMER CHEMICAL SOC
DOI: 10.1021/bi701506h
Keywords
-
Categories
Funding
- NIAID NIH HHS [AI33696, R01 AI033696, R01 AI033696-15] Funding Source: Medline
Ask authors/readers for more resources
Members of the P-lactam class of antibiotics, which inhibit the bacterial D,D-transpeptidases involved in cell wall biosynthesis, have never been used systematically in the treatment of Mycobacterium tuberculosis infections because of this organism's resistance to beta-lactams. The critical resistance factor is the constitutive production of a chromosomally encoded, Ambler class A P-lactamase, BlaC in M. tuberculosis. We show that BlaC is an extended spectrum P-lactamase (ESBL) with high levels of penicillinase and cephalosporinase activity as well as measurable activity with carbapenems, including imipenem and meropenem. We have characterized the enzyme's inhibition by three FDA-approved beta-lactamase inhibitors: sulbactam, tazobactam, and clavulanate. Sulbactarn inhibits the enzyme competitively and reversibly with respect to nitrocefin. Tazobactam inhibits the enzyme in a time-dependent manner, but the activity of the enzyme reappears due to the slow hydrolysis of the covalently acylated enzyme. In contrast, clavulanate reacts with the enzyme quickly to form hydrolytically stable, inactive forms of the enzyme that have been characterized by mass spectrometry. Clavulanate has potential to be used in combination with approved P-lactam antibiotics to treat multi-drug resistant (MDR) and extremely drug resistant (XDR) strains of M. tuberculosis.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available