In vitro antimycobacterial activity of 5-chloropyrazinamide.

Veterans Affairs Medical Center, Syracuse, New York 13210, USA.
Antimicrobial Agents and Chemotherapy (Impact Factor: 4.45). 02/1998; 42(2):462-3.
Source: PubMed

ABSTRACT 5-Chloropyrazinamide and 5-chloropyrazinoic acid were evaluated for in vitro activity against Mycobacterium tuberculosis, Mycobacterium bovis, and several nontuberculous mycobacteria by a broth dilution method. 5-Chloropyrazinamide was more active than pyrazinamide against all organisms tested. It is likely that this agent has a different mechanism of action than pyrazinamide.

  • [Show abstract] [Hide abstract]
    ABSTRACT: PZA is a unique anti-tuberculosis drug that plays a key role in shortening the TB therapy. PZA kills non-replicating persisters that other TB drugs fail to kill, and thus making it an essential drug for inclusion in any drug combinations for treating drug susceptible and drug-resistant TB such as MDR-TB. PZA acts differently from common antibiotics by inhibiting multiple targets such as energy production, trans-translation and perhaps pantothenate /coenzyme A required for persister survival. Resistance to PZA is mostly caused by mutations in the pncA gene encoding pyrazinamidase involved in conversion of the prodrug PZA to the active form POA. Mutations in the drug target RpsA are also found in some PZA-resistant strains. The recent finding that panD mutations are found in some PZA-resistant strains without pncA or rpsA mutations may suggest a third PZA resistance gene and a potential new target of PZA. Current phenotype based PZA susceptibility testing is not reliable due to false resistance, and sequencing of the pncA gene represents a more rapid, cost-effective and more reliable molecular test for PZA susceptibility testing and should be used for guiding improved treatment of MDR/XDR-TB. Finally, the story of PZA has important implications for not only TB therapy but also chemotherapy in general. PZA serves as a model prototype persister drug and hopefully a 'tipping point' that inspires new efforts at developing a new type of antibiotics or drugs that target non-replicating persisters for improved treatment of not only TB but also other persistent bacterial infections.
    01/2013; 2(4):1-12. DOI:10.1128/microbiolspec.MGM2-0023-2013
  • [Show abstract] [Hide abstract]
    ABSTRACT: A series of pyrazinamide derivatives with alkylamino substitution was designed, synthesized and tested for their ability to inhibit the growth of selected mycobacterial, bacterial and fungal strains. The target structures were prepared from the corresponding 5-chloro (1) or 6-chloropyrazine-2-carboxamide (2) by nucleophilic substitution of chlorine by various non-aromatic amines (alkylamines). To determine the influence of alkyl substitution, corresponding amino derivatives (1a, 2a) and compounds with phenylalkylamino substitution were prepared. Some of the compounds exerted antimycobacterial activity against Mycobacterium tuberculosis H37Rv significantly better than standard pyrazinamide and corresponding starting compounds (1 and 2). Basic structure-activity relationships are presented. Only weak antibacterial and no antifungal activity was detected.
    Bioorganic & medicinal chemistry letters 01/2013; DOI:10.1016/j.bmcl.2013.12.054 · 2.33 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Virtually all bacteria possess a peptidoglycan layer that is essential for their growth and survival. The β-lactams, the most widely used class of antibiotics in human history, inhibit DD-transpeptidases that catalyze the final step in peptidoglycan biosynthesis. The existence of a second class of transpeptidases, the LD-transpeptidases, was recently reported. M. tuberculosis, an infectious pathogen that causes tuberculosis (TB), is known to possess as many as five proteins with LD-transpeptidase activity. Here, for the first time, we demonstrate that loss of LD-transpeptidases LdtMt1 and LdtMt2 alters cell surface morphology, shape, size, organization of intracellular matrix, sorting of some low molecular weight proteins that are targeted to the membrane or secreted, cellular physiology, growth, virulence and resistance of M. tuberculosis to amoxicillin/clavulanate and vancomycin.
    Journal of bacteriology 01/2014; DOI:10.1128/JB.01396-13 · 2.69 Impact Factor

Full-text (2 Sources)

Available from
Jun 2, 2014