Clinical Pharmacology of the Anti-Tuberculosis Drugs
Peter D O Davies, Stephen B Gordon, Geraint Davies in Clinical Tuberculosis, 2014
Cycloserine’s MIC against M. tuberculosis ranges from 6.2 to 25 μg/mL, depending on the media, pH and the presence of d-alanine, which inhibits the drug’s activity [3,4,8,9]. It has similar activity against M. kansasii, M. intracellulare and M. avium [3]. CS generally is bacteriostatic, and the onset of action appears to be relatively slow in vitro [14]. Sustained concentrations above the MIC are required for effect in vitro because CS possesses little if any PAE [3,4]. CS disrupts d-alanine incorporation into peptidoglycan during bacterial cell wall synthesis, similar but not identical to the action of β-lactam [8,9,14]. CS targets the peptidoglycan biosynthetic enzymes d-alanine racemase (Alr) and d-alanine:d-alanine ligase (Ddl) [115]. The activity of CS has been significantly enhanced in vitro in combination with other small alanine antagonists, such as β-chloro-d-alanine, but there are no published in vivo results following up on this observation [116]. Because of limited use, CS-resistant isolates of M. tuberculosis are uncommon and cross-resistance has not been demonstrated [3].
Affinity Modification — Organic Chemistry
Dmitri G. Knorre, Valentin V. Vlassov in Affinity Modification of Biopolymers, 1989
Another mechanism initiated by the proton abstraction activates the most well-studied types of suicide reagents for pyridoxal phosphate-dependent enzymes, β- or α-fluoromethyl amino acids. In this case the net elimination of H+ and F− generates alkylating species. Thus, alanine racemase is inhibited by synthetic antibiotic β-fluoroalanine.156 Bacterial alanine racemase supplies the cells with the d-alanine isomer which is an important constituent of bacterial cell walls. Racemization proceeds most probably via α-carbanion formation. Similar proton abstraction in β-d-fluoroalanine (LIV) results in the loss of HF to yield an aminoacrylate compound which modifies nucleophiles in the enzyme active site.
Clinical Pharmacology of the Anti-Tuberculosis Drugs
Lloyd N. Friedman, Martin Dedicoat, Peter D. O. Davies in Clinical Tuberculosis, 2020
d-Cycloserine (CS) is a water-soluble weak acid (log P −2.4, pKa 4.21–8.36, MW 102.09). Terizidone (TZ) is a condensation product of two CS molecules with terephthalaldehyde, which acts as a pro-drug. CS is a natural product analog of d-alanine originating from Streptomyces garyphalus. It is a competitive inhibitor of the enzymes alanine racemase and d-alanine:d-alanine ligase, disrupting peptidoglycan synthesis.191 Wild-type MIC99s range from 8 to 32 μg/mL.85 Resistance to CS is uncommon and usually associated with mutations in the alr (alanine racemase) locus.192
Bioactive cyclic molecules and drug design
Published in Expert Opinion on Drug Discovery, 2018
Research in the latter part of the 20th century identified many classes of natural products with a majority being classified into one of four major groups from their structures and biosynthetic mechanisms. These were the terpenoids, alkaloids, polyketides, and non-ribosomal peptides (the NRPs). Although there is not enough space to show many clinically important cyclic peptides, one immunosuppressive agent should be commented on, cyclosporin (aka ciclosporin) shown in Figure 56. The structure of the compound was first reported as an iodo derivative (X-ray) in 1976 [15] and more than 30 variations have been isolated from submerged cultures of T. inflatum all synthesized by the same three enzymes with their genes being organized in a large secondary metabolite cluster. Cyclosporins have been isolated from at least 17 different fungal taxa[16], and all have the necessary ‘flexability’ to cross cell membranes and to interact with peptidyl prolyl cis/trans isomerase. Since the molecule contains D-alanine as well as two other non-proteinogenic amino acids, a D-alanine racemase is part of the genetic cluster, but will also racemize serine, Abu and leucine. The final assembly utilizes a large (15K aminoacid) NRPS complex known as CySyn, which starts with the D-Ala precursor and then follows along with the other 10 aminoacids, followed by cyclization. D-Ala in the cyclic compound is probably a method of stopping proteolytic cleavage of the active molecule.
The problem of racemization in drug discovery and tools to predict it
Published in Expert Opinion on Drug Discovery, 2019
Andrew Ballard, Stefania Narduolo, Hiwa O. Ahmad, David A. Cosgrove, Andrew G. Leach, Niklaas J. Buurma
The remaining five compounds are surveyed in more detail. Compound 26 is an inhibitor of alanine racemase, an enzyme that provides the D-Alanine required for cell wall biosynthesis [51]. It is likely that its ability to racemize is not a problem in this context. Compound 29 is a local anesthetic that can be administered intravenously and the single isomer version was promoted as providing reduced toxicity and improved efficacy [52]. In this case, studies of 29 in a range of species suggest that there is no racemization in vivo [53]. Compound 30 inhibits carbonic anhydrase and is used intraocularly via topical application and hence is likely to be protected from the racemizing medium of the plasma [54]. Antihistamine 9 had its in vivo racemization studied as described above. It is likely that the steric bulk of the three rings (two phenyl and one piperazine) that must become co-planar inhibits racemization in this case. Whereas such effects can be reproduced reasonably well by quantum mechanical calculations, the group-contribution approach that we have used here does not account for the effects of steric hindrance. Finally, 31 is a relatively recently approved treatment for Parkinson’s disease that is used in tablet form for oral administration and for which the two stereoisomers show different profiles but rates of racemization have not been reported [55].
Inhibition of O-acetylserine sulfhydrylase by fluoroalanine derivatives
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Nina Franko, Konstantinos Grammatoglou, Barbara Campanini, Gabriele Costantino, Aigars Jirgensons, Andrea Mozzarelli
Given the observed spectral changes, it can be concluded that F-Ala behaves as a substrate analog of OASS, as previously observed for β-chloroalanine30 and that the intermediate α-aminoacrylate is oriented within the active site in such a way to disfavour the reaction with any active site residue. This finding is not surprising considering that OASS has evolved to stabilise an α-aminoacrylate intermediate ready to react with the incoming nucleophilic sulfide. In addition, it has been reported for alanine racemase29,36 that the partition ratio between α-aminoacrylate hydrolysis and Michael addition on the adduct formed from the F-Ala is 820:1, a further indication of the very poor reactivity of this species in the enzyme active site.
Related Knowledge Centers
- Alanine
- Aspartic Acid
- Catalysis
- Chemical Reaction
- Cofactor
- Enzyme
- Pyridoxal Phosphate
- Amino Acid
- Substrate
- Product