Thiolactomycin and Related Analogues as Novel Anti-mycobacterial Agents Targeting KasA and KasB Condensing Enzymes inMycobacterium tuberculosis

Kremer, Laurent; Douglas, James; Baulard, Alain R.; Morehouse, Caroline B.; Guy, Mark; Alland, David; Dover, Lynn G.; Lakey, Jeremy H.; Jacobs, William R.; Brennan, Patrick J.; Minnikin, David E.; Besra, Gurdyal S.

doi:10.1074/jbc.m000569200

Cited by 237 publications

(225 citation statements)

References 39 publications

Supporting

Mentioning

216

Contrasting

Order By: Relevance

“…To date, no one has performed a gene transfer experiment demonstrating that any of these mutations confer INH resistance to susceptible strains of mycobacteria. Furthermore, the failure of overexpression of kasA in M. bovis BCG (27), M. tuberculosis, and M. smegmatis (28) to confer resistance to INH is inconsistent with a previous report (29) which raises doubts as to whether KasA plays a relevant role in INH action. Clearly, additional in vivo and in vitro studies are required in order to determine the potential role of KasA and the participation of the proposed ternary AcpMKasA-INH complex in INH and ETH resistance.…”

Section: Isoniazid (Inh)mentioning

confidence: 64%

Inhibition of InhA Activity, but Not KasA Activity, Induces Formation of a KasA-containing Complex in Mycobacteria

Kremer

Dover

Morbidoni

et al. 2003

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

(6) further demonstrated that the inhibition of mycolic acid biosynthesis mediated by INH leads to the accumulation of a saturated C 26 fatty acid within 1 h of INH treatment. By using scanning electron microscopy, it was established that M. tuberculosis treated with INH undergoes a defined order of molecular events that leads to lysis 24 h after initiation of treatment, thus after approximately one cell generation (7). The events that lead from the inhibition of mycolic acid biosynthesis and the accumulation of a saturated C 26 fatty acid to cell lysis are still poorly understood. Moreover, there exists controversy as to which enzymes of the mycolic acid biosynthetic pathway are the actual targets of INH.The mode of action of INH appears to be rather complex and requires activation by the mycobacterial catalase-peroxidase KatG (8,9). Activation of the pro-drug leads to reactive radicals that exert a toxic effect on the tubercle bacillus (9 -11). Presumably activated INH inhibits one or more targets of the mycolic acid biosynthetic pathway which eventually leads to cell death. At least two enzymes have been identified as potential targets of activated INH, the enoyl-ACP reductase InhA (12) and the ␤-ketoacyl-ACP synthase KasA (13). The inhA gene was first identified by conferring co-resistance to INH and ethionamide (ETH) after overexpression in mycobacteria (12). In addition, mutations in inhA confer resistance to both INH and ETH in drug-resistant M. tuberculosis isolates (14 -17).

show abstract

Section: Isoniazid (Inh)mentioning

confidence: 64%

Inhibition of InhA Activity, but Not KasA Activity, Induces Formation of a KasA-containing Complex in Mycobacteria

Kremer

Dover

Morbidoni

et al. 2003

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…The production of these chains is sensitive to isoniazid, thiolactomycin and triclosan in vitro . Moreover, another study showed that KasAB is the target of thiolactomycin (Kremer et al, 2000). However, since KasA is not the direct target of isoniazid, this effect may be indirect.…”

Section: Cell Wallmentioning

confidence: 99%

Comparative proteome analysis of Mycobacterium tuberculosis grown under aerobic and anaerobic conditions

Starck

Källenius

Marklund³

et al. 2004

Microbiology

135

View full text Add to dashboard Cite

Data are presented from two-dimensional (2-D) PAGE analysis of Mycobacterium tuberculosis strain Harlingen grown during aerobic and anaerobic culture, according to a modified Wayne dormancy model. M. tuberculosis cultures were grown to the transition point between exponential growth and stationary phase in the presence of oxygen (7 days) and then part of the cultures was shifted to anaerobic conditions for 16 days. Growth declined similarly during aerobic and anaerobic conditions, whereas the ATP consumption rapidly decreased in the anaerobic cultures. 2-D PAGE revealed 50 protein spots that were either unique to, or more abundant during, anaerobic conditions and 16 of these were identified by MALDI-TOF. These proteins were the a-crystalline homologue (HspX), elongation factor Tu (Tuf), GroEL2, succinyl-CoA : 3-oxoacid-CoA transferase (ScoB), mycolic acid synthase (CmaA2), thioredoxin (TrxB2), b-ketoacyl-ACP synthase (KasB), L-alanine dehydrogenase (Ald), Rv2005c, Rv2629, Rv0560c, Rv2185c and Rv3866. Some protein spots were found to be proteolytic fragments, e.g. HspX and GroEL2. These data suggest that M. tuberculosis induces expression of about 1 % of its genes in response to dormancy. INTRODUCTIONHuman tuberculosis (TB) is caused by an intracellular pathogen, Mycobacterium tuberculosis, which causes both latent and acute illness. Approximately eight million active cases are reported annually with 2 million deaths. In addition, about one-third of the global population is estimated to suffer from latent tuberculosis (Dye et al., 1999), which can be reactivated even after several decades. The fact that the bacilli can shift into a dormant state is of therapeutic importance, since this dormant state induces resistance to the two most important TB-drugs, rifampicin and isoniazide (Wayne & Sramek, 1994). One of the most challenging problems in TB research is to reveal the mechanisms behind latency.Latency is believed to involve a non-replicating persistence of mycobacteria or a very slow growth. One important condition believed to contribute to latency is reduced access to oxygen. M. tuberculosis is generally regarded as a strictly aerobic bacillus, although it can survive for a long time in a micro-aerophilic environment as long as the shift is not too abrupt (Wayne & Hayes, 1996). An in vitro model to study this persistent state is the so-called Wayne dormancy model, in which the bacteria downregulate their metabolism due to reduced access to oxygen (Wayne & Hayes, 1996). Another dormancy model utilizes nutrient starvation to induce a state where M. tuberculosis arrests growth and decreases its respiration rate (Betts et al., 2002). Recently it was demonstrated that inhibition of respiration by nitric oxide might induce a dormant state in M. tuberculosis . One should recognize, however, that the evidence linking in vitro dormant states of M. tuberculosis to human latent infection still remains circumstantial.The vaccine strain Mycobacterium bovis BCG has been reported to occasionally persist in a latent state in ...

show abstract

“…4,11 BROAD USE OF SECONDARY METABOLITES PRODUCED BY FUNGI Given the diverse array of secondary metabolites that fungi are capable of producing, the pharmaceutical industry began to focus their efforts on the screening of compounds for indications other than antiinfectives. 12,13 As microorganisms are such a prolific source of structurally diverse bioactive metabolites, the industry extended their screening programs in order to look for microbes with activity in other disease areas. As a result of this move, some of the most important products of the pharmaceutical industry were obtained.…”

Section: Introductionmentioning

confidence: 99%

Production of valuable compounds by molds and yeasts

Demain

Martens

2016

J Antibiot

View full text Add to dashboard Cite

where he has contributed in a major way to the reputation of this department for many years. He also served as an Adjunct Professor at the University of Geneva. Among Julian's areas of study and accomplishment are fungal toxins including α-sarcin, chemical synthesis of triterpenes, mode of action of streptomycin and other aminoglycoside antibiotics, biochemical mechanisms of antibiotic resistance in clinical isolates of bacteria harboring resistance plasmids, their origins and evolution, secondary metabolism of microorganisms, structure and function of bacterial ribosomes, antibiotic resistance mutations in yeast ribosomes, cloning of resistance genes from an antibiotic-producing microbe, gene cloning for industrial purposes, engineering of herbicide resistance in useful crops, bleomycin-resistance gene in clinical isolates of Staphylococcus aureus and many other topics. He has been an excellent teacher, lecturing in both English and French around the world, and has organized international courses. Julian has also served on the NIH study sections, as Editor for several international journals, and was one of the founders of the journal Plasmid. We expect the impact of Julian's accomplishments to continue into the future.

show abstract

Thiolactomycin and Related Analogues as Novel Anti-mycobacterial Agents Targeting KasA and KasB Condensing Enzymes inMycobacterium tuberculosis

Cited by 237 publications

References 39 publications

Inhibition of InhA Activity, but Not KasA Activity, Induces Formation of a KasA-containing Complex in Mycobacteria

Inhibition of InhA Activity, but Not KasA Activity, Induces Formation of a KasA-containing Complex in Mycobacteria

Comparative proteome analysis of Mycobacterium tuberculosis grown under aerobic and anaerobic conditions

Production of valuable compounds by molds and yeasts

Contact Info

Product

Resources

About