ly-146032 and Gram-Positive-Bacterial-Infections

Antibiotic resistance is a critical global health care crisis requiring urgent action to develop more effective antibiotics. Utilizing the hydrophobic scaffold of xanthone, we identified three components that mimicked the action of an antimicrobial cationic peptide to produce membrane-targeting antimicrobials. Compounds 5c and 6, which contain a hydrophobic xanthone core, lipophilic chains, and cationic amino acids, displayed very promising antimicrobial activity against multidrug-resistant Gram-positive bacteria, including MRSA and VRE, rapid time-kill, avoidance of antibiotic resistance, and low toxicity. The bacterial membrane selectivity of these molecules was comparable to that of several membrane-targeting antibiotics in clinical trials. 5c and 6 were effective in a mouse model of corneal infection by S. aureus and MRSA. Evidence is presented indicating that 5c and 6 target the negatively charged bacterial membrane via a combination of electrostatic and hydrophobic interactions. These results suggest that 5c and 6 have significant promise for combating life-threatening infections.

Topics: Amino Acids; Animals; Anti-Bacterial Agents; Cell Membrane; Drug Resistance, Multiple, Bacterial; Gram-Positive Bacterial Infections; Magnetic Resonance Spectroscopy; Mice; Microbial Sensitivity Tests; Rabbits; Structure-Activity Relationship; Unilamellar Liposomes; Xanthones

Synthetic studies of the antimicrobial secondary metabolite thiomuracin A (1) were initiated to improve chemical stability and physicochemical properties. Functional group modifications of 1 included removing the C2-C7 side chain, derivatizing the C84 epoxide region, and altering the C44 hydroxyphenylalanine motif. The resulting derivatives simplified and stabilized the chemical structure and were evaluated for antibacterial activity relative to 1. The simplified structure and improved organic solubility of the derivatives facilitated isolation yields from fermentation broths and simplified the procedures involved for the process. These advancements increased material supply for continued medicinal chemistry optimization and culminated in the identification of 2, a structurally simplified and chemically stable analogue of 1 which retained potent antibiotic activity.

Topics: Animals; Anti-Bacterial Agents; Clostridioides difficile; Crystallography, X-Ray; Enterococcus; Escherichia coli; Escherichia coli Proteins; Female; Gram-Positive Bacterial Infections; Male; Mice; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Peptide Elongation Factor Tu; Peptides, Cyclic; Protein Synthesis Inhibitors; Rats; Rats, Sprague-Dawley; Staphylococcus aureus; Streptococcus pyogenes; Structure-Activity Relationship; Thiazoles; Transcription, Genetic

4-Aminothiazolyl analogues of the antibiotic natural product GE2270 A (1) were designed, synthesized, and optimized for their activity against Gram positive bacterial infections. Optimization efforts focused on improving the physicochemical properties (e.g., aqueous solubility and chemical stability) of the 4-aminothiazolyl natural product template while improving the in vitro and in vivo antibacterial activity. Structure-activity relationships were defined, and the solubility and efficacy profiles were improved over those of previous analogues and 1. These studies identified novel, potent, soluble, and efficacious elongation factor-Tu inhibitors, which bear cycloalkylcarboxylic acid side chains, and culminated in the selection of development candidates amide 48 and urethane 58.

Topics: Animals; Anti-Bacterial Agents; Area Under Curve; Carboxylic Acids; Crystallography, X-Ray; Drug Resistance, Bacterial; Female; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Male; Mice; Microbial Sensitivity Tests; Models, Molecular; Molecular Conformation; Mutation; Peptides, Cyclic; Rats; Rats, Sprague-Dawley; Sepsis; Solubility; Stereoisomerism; Structure-Activity Relationship; Thiazoles

In this study, we investigated the clonal emergence of daptomycin-resistant Enterococcus faecium strains isolated from a patient with leukocyte adhesion deficiency syndrome. The resistance mechanism in these strains is independent of either equivalent point mutations previously described for Staphylococcus aureus or daptomycin inactivation mechanisms identified in soil bacteria.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Daptomycin; DNA, Bacterial; Drug Resistance, Bacterial; Electrophoresis, Gel, Pulsed-Field; Enterococcus faecium; Gram-Positive Bacterial Infections; Humans; Leukocyte-Adhesion Deficiency Syndrome; Microbial Sensitivity Tests; Point Mutation; Polymerase Chain Reaction; Vancomycin

Between 1 September 2005 and 30 June 2006, 19 medical centers collected 4,180 isolates recovered from clinical specimens from patients in intensive care units (ICUs) in Canada. The 4,180 isolates were collected from 2,292 respiratory specimens (54.8%), 738 blood specimens (17.7%), 581 wound/tissue specimens (13.9%), and 569 urinary specimens (13.6%). The 10 most common organisms isolated from 79.5% of all clinical specimens were methicillin-susceptible Staphylococcus aureus (MSSA) (16.4%), Escherichia coli (12.8%), Pseudomonas aeruginosa (10.0%), Haemophilus influenzae (7.9%), coagulase-negative staphylococci/Staphylococcus epidermidis (6.5%), Enterococcus spp. (6.1%), Streptococcus pneumoniae (5.8%), Klebsiella pneumoniae (5.8%), methicillin-resistant Staphylococcus aureus (MRSA) (4.7%), and Enterobacter cloacae (3.9%). MRSA made up 22.3% (197/884) of all S. aureus isolates (90.9% of MRSA were health care-associated MRSA, and 9.1% were community-associated MRSA), while vancomycin-resistant enterococci (VRE) made up 6.7% (11/255) of all enterococcal isolates (88.2% of VRE had the vanA genotype). Extended-spectrum beta-lactamase (ESBL)-producing E. coli and K. pneumoniae occurred in 3.5% (19/536) and 1.8% (4/224) of isolates, respectively. All 19 ESBL-producing E. coli isolates were PCR positive for CTX-M, with bla CTX-M-15 occurring in 74% (14/19) of isolates. For MRSA, no resistance against daptomycin, linezolid, tigecycline, and vancomycin was observed, while the resistance rates to other agents were as follows: clarithromycin, 89.9%; clindamycin, 76.1%; fluoroquinolones, 90.1 to 91.8%; and trimethoprim-sulfamethoxazole, 11.7%. For E. coli, no resistance to amikacin, meropenem, and tigecycline was observed, while resistance rates to other agents were as follows: cefazolin, 20.1%; cefepime, 0.7%; ceftriaxone, 3.7%; gentamicin, 3.0%; fluoroquinolones, 21.1%; piperacillin-tazobactam, 1.9%; and trimethoprim-sulfamethoxazole, 24.8%. Resistance rates for P. aeruginosa were as follows: amikacin, 2.6%; cefepime, 10.2%; gentamicin, 15.2%; fluoroquinolones, 23.8 to 25.5%; meropenem, 13.6%; and piperacillin-tazobactam, 9.3%. A multidrug-resistant (MDR) phenotype (resistance to three or more of the following drugs: cefepime, piperacillin-tazobactam, meropenem, amikacin or gentamicin, and ciprofloxacin) occurred frequently in P. aeruginosa (12.6%) but uncommonly in E. coli (0.2%), E. cloacae (0.6%), or K. pneumoniae (0%). In conclusion, S. aureus (MSSA and MRSA), E.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; beta-Lactamases; Canada; Drug Resistance, Bacterial; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Intensive Care Units; Male; Microbial Sensitivity Tests; Middle Aged; Population Surveillance

Telavancin is an investigational, rapidly bactericidal lipoglycopeptide antibiotic that is being developed to treat serious infections caused by gram-positive bacteria. A baseline prospective surveillance study was conducted to assess telavancin activity, in comparison with other agents, against contemporary clinical isolates collected from 2004 to 2005 from across the United States. Nearly 4,000 isolates were collected, including staphylococci, enterococci, and streptococci (pneumococci, beta-hemolytic, and viridans). Telavancin had potent activity against Staphylococcus aureus and coagulase-negative staphylococci (MIC range, 0.03 to 1.0 microg/ml), independent of resistance to methicillin or to multiple agents. Telavancin activity was particularly potent against all streptococcal groups (MIC(90)s, 0.03 to 0.12 microg/ml). Telavancin had excellent activity against vancomycin-susceptible enterococci (MIC(90), 1 microg/ml) and was active against VanB strains of vancomycin-resistant enterococci (MIC(90), 2 microg/ml) but less active against VanA strains (MIC(90), 8 to 16 microg/ml). Telavancin also demonstrated activity against vancomycin-intermediate S. aureus and vancomycin-resistant S. aureus strains (MICs, 0.5 microg/ml to 1.0 microg/ml and 1.0 microg/ml to 4.0 microg/ml, respectively). These data may support the efficacy of telavancin for treatment of serious infections with a wide range of gram-positive organisms.

Topics: Aminoglycosides; Anti-Bacterial Agents; Drug Resistance, Bacterial; Enterococcus; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Microbial Sensitivity Tests; Prospective Studies; Staphylococcus aureus; Streptococcus; Streptococcus pneumoniae; United States

The in vitro activity of telavancin was tested against 743 predominantly antimicrobial-resistant, gram-positive isolates. Telavancin was highly active against methicillin-resistant staphylococci (MIC(90), 0.5 to 1 microg/ml), streptococci (all MICs, < or =0.12 microg/ml), and VanB-type enterococci (all MICs, < or =2 microg/ml). Time-kill studies demonstrated the potent bactericidal activity of telavancin.

Topics: Aminoglycosides; Anti-Bacterial Agents; Drug Resistance, Bacterial; Enterococcus; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; In Vitro Techniques; Lipoglycopeptides; Methicillin Resistance; Microbial Sensitivity Tests; Staphylococcus; Streptococcus

MICs of daptomycin, linezolid, and vancomycin against 212 isolates, including Listeria monocytogenes and Pediococcus, Leuconostoc, Rhodococcus, and Nocardia spp., were determined by the broth microdilution method; daptomycin MICs were also determined by the Etest. Except with those for Leuconostoc spp., daptomycin Etest MICs showed >90% agreement with MICs obtained by the broth microdilution method.

Topics: Culture Media; Daptomycin; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Microbial Sensitivity Tests

The in vitro activity of telavancin was tested against 620 gram-positive isolates. For staphylococci, MICs at which 50 and 90% of isolates were inhibited (MIC(50) and MIC(90)) were both 0.25 microg/ml, irrespective of methicillin resistance. MIC(50) and MIC(90) were 0.25 and 0.5 microg/ml for vancomycin-susceptible enterococci and 1 and 2 microg/ml for vancomycin-resistant enterococci, respectively. Streptococcus pneumoniae, group A and B beta-hemolytic streptococci, and viridans streptococci were inhibited by < or =0.12 microg/ml.

Topics: Aminoglycosides; Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Europe; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Methicillin Resistance; Microbial Sensitivity Tests; Staphylococcus aureus; Streptococcus agalactiae; Streptococcus pyogenes; Vancomycin Resistance; Viridans Streptococci