Inhibitors of nucleic acid synthesis have several modes of action and fall into two categories: those that inhibit the synthesis of purine and pyrimidine nucleotides; those that inhibit synthesis at the polymerization level. Creative Biolabs has focused on the development of new antibiotics for many years and has established excellent platforms for drug development. We provide the identification services of new inhibitors of nucleic acid synthesis to meet the diverse needs of our customers.

Inhibitors of DNA Gyrase

Antibacterial activity of drugs targeting the DNA gyrase enzyme follows one of two mechanisms. They either inhibit the catalytic activity of the enzyme by binding to the active site or they stabilize the covalent enzyme-DNA complex that is formed during the reaction. Fluoroquinolones work by stabilizing the enzyme-DNA complex and thus interrupting the religation step. The targets of the fluoroquinolones are DNA gyrase and DNA topoisomerase IV, both belonging to the type II topoisomerases. The target of the quinolones is DNA gyrase in gram-negative bacteria while in gram-positive bacteria the target is topoisomerase IV.

Quinolones are the highly effective broad-spectrum antibiotics that target DNA gyrase as their site of action. The first generation drugs which include the first quinolone antibiotic nalidixic acid achieves only minimal serum concentration and so is not of much use. Second generation quinolone antibiotics including norfloxacin and ciprofloxacin are effective against gram-negative bacteria. Third generation quinolones include levofloxacin are effective against both gram-negative and gram-positive bacteria while fourth-generation quinolones, which include trovafloxacin, moxifloxacin, and gemifloxacin and have the broadest spectrum of activity.

Inhibitors of DNA gyrase. Fig.1 Inhibitors of DNA gyrase. (Bhattacharjee, 2016)

Inhibitors of RNA Polymerase

Rifamycins form a family of antibiotics that inhibit RNA synthesis by binding to RNA polymerase, the enzyme that catalyzes the process of transcription. The antibiotic binds to the β-subunit of RNA polymerase within the DNA/RNA channel. It inhibits RNA synthesis by directly blocking the path of the elongating RNA when the transcript becomes 2 to 3 nucleotides in length. Rifamycins are broad-spectrum bactericidal antibiotics that inhibit both gram-negative and gram-positive bacteria including obligate intracellular bacteria. They can easily cross the bacterial cell wall and membrane and bind to the target. It is for this reason that rifampicin is effective in the treatment of mycobacterial diseases, such as tuberculosis and leprosy.

Antibiotics that inhibit RNA synthesis. Fig.2 Antibiotics that inhibit RNA synthesis. (Bhattacharjee, 2016)

Services

Based on structural information, Creative Biolabs provides three main methods to identify new inhibitors of nucleic acid synthesis.

  • The first approach is ‘substrate-and known inhibitor design’ where a known inhibitor or cofactor is modified to improve binding affinity.
  • In the second approach, de novo design, a molecule is designed from scratch to bind in the active site. Fragments are docked into subsites, and then joined to create full molecules. These molecules are scored and ranked in silico based on the interactions present with the target protein.
  • The third approach is the docking of small molecule libraries into the desired target crystal structure.

Creative Biolabs' new antibiotic development services offer numerous options to meet a variety of research needs. Our team provides you with outstanding support and meets your specific needs with a professional technology platform. If you are interested in our services, please contact us for more details.

Reference

  1. Bhattacharjee, M. Antibiotics that inhibit nucleic acid synthesis. Chemistry of Antibiotics and Related Drugs. Springer, Cham, 2016: 109-128.

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