Development potential of rifalazil

Abstract

Rifalazil represents a new generation of ansamycins that contain a unique four-ring structure. Originally rifalazil was developed as a therapeutic agent to replace rifampin as part of a multiple drug regimen in the treatment of tuberculosis. As a result of its superior antimicrobial activity and high intracellular levels, rifalazil has potential to treat indications caused by the intracellular pathogen, Chlamydia trachomatis, which causes non-gonococcal urethritis and cervicitis, often leading to pelvic inflammatory disease. Rifalazil also has potential to treat the related microorganism, Chlamydia pneumoniae, which may be involved in chronic inflammatory processes thought to be partly responsible for atherosclerosis. Due to its favourable antimicrobial spectrum and other positive attributes, rifalazil may also prove valuable in the treatment of gastric ulcer disease, caused by Helicobacter pylori, and antibiotic-associated colitis, the result of toxin production following the growth of Clostridium difficile in the colon. The potential value of rifalazil in the treatment of these indications will be assessed in human clinical trials.

In Vitro Time-kill Activities of Rifalazil, Alone and in Combination with Vancomycin, against Logarithmic and Stationary Cultures of Staphylococcus aureus

“…Rifamycins inhibit the b subunit of bacterial RNA polymerase encoded by the rpoB gene, and have excellent antibacterial activity against a wide range of Gram-positive and some Gram-negative organisms [1]. Rifalazil, also known as KRM-1648 and ABI-1648, represents the next generation of rifamycins, with improved potency against certain pathogens, and lacking the CYP450 isozyme induction that causes undesirable drug-drug interactions for rifampicin [1].…”

“…Rifalazil, also known as KRM-1648 and ABI-1648, represents the next generation of rifamycins, with improved potency against certain pathogens, and lacking the CYP450 isozyme induction that causes undesirable drug-drug interactions for rifampicin [1]. Although rifampicin and rifalazil are bactericidal in vitro and show efficacy in animal models of infectious disease [1], resistance to these drugs occurs at high frequency among Staphylococci and Streptococci (10 Ϫ8 /cell/generation), precluding their use as monotherapy for many infections. Resistance mutations map to the the rpoB gene [2].…”

Enhanced Activity of Rifalazil in Combination with Levofloxacin, Linezolid, or Mupirocin against Staphylococcus aureus In Vitro

“…Rifampicin and other rifamycins inhibit bacteria by targeting the b subunit of RNA polymerase, and are active against a wide range of Gram-positive and certain Gramnegative organisms [1]. In vitro experiments have demonstrated the bactericidal nature of this class of drugs [1].…”

“…In vitro experiments have demonstrated the bactericidal nature of this class of drugs [1]. A new generation of rifamycins, represented by rifalazil, also known as KRM-1648 and more recently, ABI-1648, has improved properties, including increased potency and lack of P450 induction [1].…”

“…In vitro experiments have demonstrated the bactericidal nature of this class of drugs [1]. A new generation of rifamycins, represented by rifalazil, also known as KRM-1648 and more recently, ABI-1648, has improved properties, including increased potency and lack of P450 induction [1]. However, resistance to both rifampicin and rifalazil occurs at high frequency (approximately 10 Ϫ8 /bacterial generation) and precludes their use as a monotherapy for infections with high bacterial cell density.…”