ABSTRACT
We report novel polymyxin analogues with improved antibacterial in vitro potency against polymyxin resistant recent clinical isolates of Acinetobacter baumannii and Pseudomonas aeruginosa . In addition, a human renal cell in vitro assay (hRPTEC) was used to inform structure-toxicity relationships and further differentiate analogues. Replacement of the Dab-3 residue with a Dap-3 in combination with a relatively polar 6-oxo-1-phenyl-1,6-dihydropyridine-3-carbonyl side chain as a fatty acyl replacement yielded analogue 5x, which demonstrated an improved in vitro antimicrobial and renal cytotoxicity profiles relative to polymyxin B (PMB). However, in vivo PK/PD comparison of 5x and PMB in a murine neutropenic thigh model against P. aeruginosa strains with matched MICs showed that 5x was inferior to PMB in vivo, suggesting a lack of improved therapeutic index in spite of apparent in vitro advantages.
Subject(s)
Cross Infection/drug therapy , Drug Discovery , Drug Resistance, Multiple/drug effects , Gram-Negative Bacteria/drug effects , Polymyxins/chemistry , Polymyxins/pharmacology , beta-Alanine/analogs & derivatives , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/toxicity , Dogs , Female , Gram-Negative Bacteria/physiology , Humans , Male , Microbial Sensitivity Tests , Polymyxins/pharmacokinetics , Polymyxins/toxicity , Rats , beta-Alanine/chemistryABSTRACT
A novel series of 3-O-carbamoyl erythromycin A derived analogs, labeled carbamolides, with activity versus resistant bacterial isolates of staphylococci (including macrolide and oxazolidinone resistant strains) and streptococci are reported. An (R)-2-aryl substituent on a pyrrolidine carbamate appeared to be critical for achieving potency against resistant strains. Crystal structures showed a distinct aromatic interaction between the (R)-2-aryl (3-pyridyl for 4d) substituent on the pyrrolidine and G2484 (G2505, Escherichia coli) of the Deinococcus radiodurans 50S ribosome (3.2Å resolution).
Subject(s)
Anti-Bacterial Agents/chemistry , Erythromycin/analogs & derivatives , Methylurea Compounds/chemistry , Staphylococcus/isolation & purification , Streptococcus/isolation & purification , Anti-Bacterial Agents/chemical synthesis , Binding Sites , Crystallography, X-Ray , Deinococcus/metabolism , Drug Resistance, Bacterial , Erythromycin/chemical synthesis , Escherichia coli/metabolism , Microbial Sensitivity Tests , Protein Structure, Tertiary , Pyrrolidines/chemistry , Ribosome Subunits, Large, Bacterial/chemistry , Ribosome Subunits, Large, Bacterial/metabolism , Staphylococcus/drug effects , Streptococcus/drug effectsABSTRACT
A novel series of monocarbam compounds exhibiting promising antibacterial activity against multidrug resistant Gram-negative microorganisms is reported, along with the synthesis of one such molecule MC-1 (1). Also reported are structure-activity relationships associated with the in vitro and in vivo efficacy of 1 and related analogues in addition to the hydrolytic stability of such compounds and possible implications thereof.
ABSTRACT
Respiratory tract bacterial strains are becoming increasingly resistant to currently marketed macrolide antibiotics. The current alternative telithromycin (1) from the newer ketolide class of macrolides addresses resistance but is hampered by serious safety concerns, hepatotoxicity in particular. We have discovered a novel series of azetidinyl ketolides that focus on mitigation of hepatotoxicity by minimizing hepatic turnover and time-dependent inactivation of CYP3A isoforms in the liver without compromising the potency and efficacy of 1.
