ABSTRACT
SAR studies and optimization of various modified Hygromycin A fluoroalkyl ethers, which led to the discovery of the highly potent 4'-(2-cyclopropyl-2-fluoroethyl ether) antibacterial CE-156811 (1) derived from truncation of the ribose ring and difluorination of the phenyl found in Hygromycin A, are discussed.
Subject(s)
Anti-Bacterial Agents/chemistry , Cinnamates/chemistry , Dioxoles/chemistry , Hygromycin B/analogs & derivatives , Administration, Oral , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacokinetics , Dogs , Drug Evaluation, Preclinical , Haplorhini , Hygromycin B/chemistry , Mice , Microbial Sensitivity Tests , Rats , Structure-Activity RelationshipABSTRACT
Infections caused by multidrug-resistant Gram-negative pathogens play a major role in the morbidity and mortality of hospitalized patients. The rise of resistance to current antibiotic therapies has made the discovery of new agents urgent. One of the major antibiotic resistance mechanisms utilized by more than 15 species of Gram-negative bacterial cells is the Resistance Nodulation Division (RND) efflux pump, which eliminates several classes of antibiotics such as penicillins and cephalosporin macrolides aminoglycosides, fluoroquinolonesx and tetracyclines. Here we describe a multistep process to identify compounds that inhibit the RND-type efflux pumps. This involves measuring the inhibition of accumulation of ethidium bromide in E. coli or Haemophilus influenzae cells and confirming that the inhibition is specific for the efflux pumps by using genetic constructs and biochemical methods to measure nonspecific inhibition due to e.g. intrinsic antibacterial activity or membrane disruption. In whole bacterial cells synergism antagonism or indifference of the combination of an antibiotic with the putative inhibitor is determined and this is then confirmed by quantitating viable bacterial cells in liquid culture over 24 h.
Subject(s)
Anti-Bacterial Agents/analysis , Biological Transport, Active/drug effects , Enzyme Inhibitors/analysis , Multidrug Resistance-Associated Proteins/antagonists & inhibitors , Anti-Bacterial Agents/isolation & purification , Anti-Bacterial Agents/pharmacology , Bacterial Outer Membrane Proteins/antagonists & inhibitors , Bacterial Proteins/analysis , Bacterial Proteins/antagonists & inhibitors , Drug Resistance, Bacterial/drug effects , Enzyme Inhibitors/isolation & purification , Enzyme Inhibitors/pharmacology , Escherichia coli/drug effects , Ethidium/metabolism , Haemophilus influenzae/drug effects , Humans , Microbial Sensitivity TestsABSTRACT
We evaluated a novel truncated hygromycin A analog in which the furanose ring was replaced with a 2-fluoro-2-cyclopropylethyl substituent for its activity against multidrug resistant gram-positive bacteria and compared its activity to the activities of linezolid, quinupristin-dalfopristin, and vancomycin. CE-156811 demonstrated robust in vitro activity against gram-positive bacteria that was comparable to that of linezolid.
Subject(s)
Anti-Bacterial Agents/pharmacology , Cinnamates/pharmacology , Dioxoles/pharmacology , Gram-Positive Bacteria/drug effects , Hygromycin B/analogs & derivatives , Acetamides/pharmacology , Anti-Bacterial Agents/chemistry , Cinnamates/chemistry , Dioxoles/chemistry , Drug Resistance, Multiple, Bacterial , Gram-Negative Bacteria/drug effects , Gram-Negative Bacteria/isolation & purification , Gram-Positive Bacteria/isolation & purification , Humans , Hygromycin B/chemistry , Hygromycin B/pharmacology , In Vitro Techniques , Linezolid , Microbial Sensitivity Tests , Molecular Structure , Oxazolidinones/pharmacologyABSTRACT
A new antibiotic, CJ-17,572 (I) was isolated from the fermentation broth of a fungus Pezicula sp. CL11877. The structure of I was determined to be a new equisetin derivative by spectroscopic analyses. The compound inhibits the growth of multi-drug resistant Staphylococcus aureus and Enterococcusfaecalis with IC50s of 10 and 20 microg/ml, respectively.
