Favrot L

References (3)

Title : Inactivation of the Mycobacterium tuberculosis antigen 85 complex by covalent, allosteric inhibitors - Favrot_2014_J.Biol.Chem_289_25031
Author(s) : Favrot L , Lajiness DH , Ronning DR
Ref : Journal of Biological Chemistry , 289 :25031 , 2014
Abstract : The rise of multidrug-resistant and totally drug-resistant tuberculosis and the association with an increasing number of HIV-positive patients developing tuberculosis emphasize the necessity to find new antitubercular targets and drugs. The antigen 85 (Ag85) complex from Mycobacterium tuberculosis plays important roles in the biosynthesis of major components of the mycobacterial cell envelope. For this reason, Ag85 has emerged as an attractive drug target. Recently, ebselen was identified as an effective inhibitor of the Ag85 complex through covalent modification of a cysteine residue proximal to the Ag85 active site and is therefore a covalent, allosteric inhibitor. To expand the understanding of this process, we have solved the x-ray crystal structures of Ag85C covalently modified with ebselen and other thiol-reactive compounds, p-chloromercuribenzoic acid and iodoacetamide, as well as the structure of a cysteine to glycine mutant. All four structures confirm that chemical modification or mutation at this particular cysteine residue leads to the disruption of the active site hydrogen-bonded network essential for Ag85 catalysis. We also describe x-ray crystal structures of Ag85C single mutants within the catalytic triad and show that a mutation of any one of these three residues promotes the same conformational change observed in the cysteine-modified forms. These results provide evidence for active site dynamics that may afford new strategies for the development of selective and potent Ag85 inhibitors.
ESTHER : Favrot_2014_J.Biol.Chem_289_25031
PubMedSearch : Favrot_2014_J.Biol.Chem_289_25031
PubMedID: 25028518
Gene_locus related to this paper: myctu-a85c

Title : Mechanism of inhibition of Mycobacterium tuberculosis antigen 85 by ebselen - Favrot_2013_Nat.Commun_4_2748
Author(s) : Favrot L , Grzegorzewicz AE , Lajiness DH , Marvin RK , Boucau J , Isailovic D , Jackson M , Ronning DR
Ref : Nat Commun , 4 :2748 , 2013
Abstract : The increasing prevalence of drug-resistant tuberculosis highlights the need for identifying new antitubercular drugs that can treat these infections. The antigen 85 (Ag85) complex has emerged as an intriguing mycobacterial drug target due to its central role in synthesizing major components of the inner and outer leaflets of the mycobacterial outer membrane. Here we identify ebselen (EBS) as a potent inhibitor of the Mycobacterium tuberculosis Ag85 complex. Mass spectrometry data show that EBS binds covalently to a cysteine residue (C209) located near the Ag85C active site. The crystal structure of Ag85C in the presence of EBS shows that C209 modification restructures the active site, thereby disrupting the hydrogen-bonded network within the active site that is essential for enzymatic activity. C209 mutations display marked decreases in enzymatic activity. These data suggest that compounds using this mechanism of action will strongly inhibit the Ag85 complex and minimize the selection of drug resistance.
ESTHER : Favrot_2013_Nat.Commun_4_2748
PubMedSearch : Favrot_2013_Nat.Commun_4_2748
PubMedID: 24193546
Gene_locus related to this paper: myctu-a85c

Title : Targeting the mycobacterial envelope for tuberculosis drug development - Favrot_2012_Expert.Rev.Anti.Infect.Ther_10_1023
Author(s) : Favrot L , Ronning DR
Ref : Expert Rev Anti Infect Ther , 10 :1023 , 2012
Abstract : The bacterium that causes tuberculosis, Mycobacterium tuberculosis, possesses a rather unique outer membrane composed largely of lipids that possess long-chain and branched fatty acids, called mycolic acids. These lipids form a permeability barrier that prevents entry of many environmental solutes, thereby making these bacteria acid-fast and able to survive extremely hostile surroundings. Antitubercular drugs must penetrate this layer to reach their target. This review highlights drug development efforts that have added to the slowly growing tuberculosis drug pipeline, identified new enzyme activities to target with drugs and increased the understanding of important biosynthetic pathways for mycobacterial outer membrane and cell wall core assembly. In addition, a portion of this review looks at discovery efforts aimed at weakening this barrier to decrease mycobacterial virulence, decrease fitness in the host or enhance the efficacy of the current drug repertoire by disrupting the permeability barrier.
ESTHER : Favrot_2012_Expert.Rev.Anti.Infect.Ther_10_1023
PubMedSearch : Favrot_2012_Expert.Rev.Anti.Infect.Ther_10_1023
PubMedID: 23106277