Efficacy of Novel Rifamycin Derivatives against Rifamycin-Sensitive and -Resistant Staphylococcus aureus Isolates in Murine Models of Infection

Abstract

Novel rifamycins (new chemical entities [NCEs]) having MICs of 0.002 to 0.03 g/ml against Staphylococcus aureus and retaining some activity against rifampin-resistant mutants were tested for in vivo efficacy against susceptible and rifampin-resistant strains of S. aureus. Rifalazil and rifampin had a 50% effective dose (ED 50 ) of 0.06 mg/kg of body weight when administered as a single intravenous (i.v.) dose in a murine septicemia model against a susceptible strain of S. aureus. The majority of NCEs showed efficacy at a lower i.v. dose (0.003 to 0.06 mg/kg). In addition, half of the NCEs tested for oral efficacy had ED 50 s in the range of 0.015 to 0.13 mg/kg, i.e., lower or equivalent to the oral ED 50 s of rifampin and rifalazil. NCEs were also tested in the septicemia model against a rifampin-resistant strain of S. aureus. Twenty-four of 169 NCEs were efficacious when administered as a single oral dose of 80 mg/kg. These NCEs were examined in the murine thigh infection model against a susceptible strain of S. aureus. Several NCEs dosed by intraperitoneal injection at 0.06 mg/kg caused a significant difference in bacterial titer compared with placebo-treated animals. No NCEs showed efficacy in the thigh model against a highly rifampin-resistant strain. However, several NCEs showed an effect when tested against a partially rifampin-resistant strain. The NCEs having a 25-hydroxyl moiety were more effective as a group than their 25-O-acetyl counterparts. These model systems defined candidate NCEs as components of potential combination therapies to treat systemic infections or as monotherapeutic agents for topical applications.Rifalazil [3Ј-hydroxy-5Ј-(4-isobutyl-1-piperazinyl) benzoxazinorifamycin], also referred to as KRM-1648 or ABI-1648, is a rifamycin derivative with exceptionally low MICs against gram-positive bacteria (7,19), Helicobacter pylori (1), and Chlamydia (9,18,21,22). The potency of rifalazil and the other rifamycins derives from their specific inhibition of bacterial RNA polymerase (6). Preclinical animal studies suggest that rifalazil has efficacy against Chlamydia pneumoniae (9), Clostridium difficile (2), Mycobacterium tuberculosis (8,19,20), and Staphylococcus aureus (7). In addition, rifalazil has been tested in phase 2 human clinical trials for the treatment of tuberculosis (5) L-992b, 2004). One of the attributes of rifamycins, including rifalazil, is the propensity for resistance to develop as a result of the occurrence of mutations in the rpoB gene. These mutations cause modifications in the binding site of the target enzyme, the ␤ subunit of RNA polymerase, in pathogens such as M. tuberculosis (13, 17, 25, 26), S. aureus (23, 24), and Streptococcus pyogenes (3). Thus, rifamycins have been confined primarily to multiple-drug therapy where resistance development is less of an issue.Recently, we described a collection of over 700 novel rifamycins which are related in structure to rifalazil. More than 50% of these new chemical entities (NCEs) are more active against gram-positive bacteri...

Rifalazil and Derivative Compounds Show Potent Efficacy in a Mouse Model of H. pylori Colonization

“…3, it appears that there is a systemic component that contributes to efficacy. It is very possible, therefore, that differences between NCEs result from pharmacokinetic differences among these compounds [14,15]. These results are in agreement with studies which indicate that both topical and a systemic component must be considered in efficacy in eradicating H. pylori [16].…”

Efficacy of a Novel Rifamycin Derivative, ABI-0043, against Staphylococcus aureus in an Experimental Model of Foreign-Body Infection

“…This new compound differs from rifampin in that it contains a four-ring, planar structure (Fig. 1), which may account for its greater lipophilicity, tissue penetration, and longer half-life (17,18). An important distinguishing characteristic compared with rifampin is that ABI-0043 lacks significant interactions with liver microsomal enzymes (18).…”

“…These compounds have even more potent activity in vitro than rifampin or rifalazil and retain some activity against rifampin-resistant strains (13). They are also effective at lower doses than rifampin or rifalazil in murine models of infection (17). Like rifalazil, the NCEs do not interact with P450 CYP 3A4 (19), whereas the induction of P450 enzymes by rifampin has been shown to be responsible for a number of drug-drug interactions (16,32).…”

In vitro and in vivo activities of echinomycin against clinical isolates of Staphylococcus aureus

“…The test antimicrobial agents were administered subcutaneously in a single dose 1 h after inoculation, with 10 mice in each dosage group of antimicrobial agents. The number of surviving mice for each dosage was recorded 7 days after the infection, and the mean effective dose sufficient to protect 50% of the mice (ED 50 ) 21,22 was determined from the final survival rates using GraphPad PRISM software (GraphPad Software, Inc., San Diego, CA, USA).…”