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1.
J Med Chem ; 67(11): 9465-9484, 2024 Jun 13.
Article in English | MEDLINE | ID: mdl-38753983

ABSTRACT

Clostridioides difficile (C. difficile) is one of the leading causes of healthcare-associated infections worldwide. The increasing incidence of strains resistant to currently available therapies highlights the need for alternative treatment options with a novel mode of action. Oxazolidinones that are connected to a quinolone moiety with a pyrrolidine linker, such as compound 1, are reported to exhibit potent broadspectrum antibacterial activity. In an effort to optimize this class of compounds for the treatment of C. difficile infection (CDI), we have identified cadazolid (9), a first-in-class quinoxolidinone antibiotic, which is a potent inhibitor of C. difficile protein synthesis. In order to achieve narrow-spectrum coverage of clinically most relevant strains without affecting the gut microbiota, an emphasis was placed on abolishing activity against commensals of the intestinal microbiome while retaining good coverage of pathogenic C. difficile, including hypervirulent and epidemic strains.


Subject(s)
Anti-Bacterial Agents , Clostridioides difficile , Clostridium Infections , Microbial Sensitivity Tests , Structure-Activity Relationship , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/therapeutic use , Anti-Bacterial Agents/chemical synthesis , Clostridioides difficile/drug effects , Clostridium Infections/drug therapy , Animals , Humans , Drug Discovery , Gastrointestinal Microbiome/drug effects , Mice , Oxazolidinones
2.
Front Microbiol ; 11: 1681, 2020.
Article in English | MEDLINE | ID: mdl-32793157

ABSTRACT

Pseudomonas aeruginosa is an opportunistic human pathogen and a leading cause of nosocomial infections. Due to its high intrinsic and adaptive resistance to antibiotics, infections caused by this organism are difficult to treat and new therapeutic options are urgently needed. Novel peptidomimetic antibiotics that target outer membrane (OM) proteins have shown great promise for the treatment of P. aeruginosa infections. Here, we have performed genome-wide mutant fitness profiling using transposon sequencing (Tn-Seq) to identify resistance determinants against the recently described peptidomimetics L27-11, compounds 3 and 4, as well as polymyxin B2 (PMB) and colistin (COL). We identified a set of 13 core genes that affected resistance to all tested antibiotics, many of which encode enzymes involved in the modification of the lipopolysaccharide (LPS) or control their expression. We also identified fitness determinants that are specific for antibiotics with similar structures that may indicate differences in their modes of action. These results provide new insights into resistance mechanisms against these peptide antibiotics, which will be important for future clinical development and efforts to further improve their potency.

3.
J Antimicrob Chemother ; 75(6): 1518-1524, 2020 06 01.
Article in English | MEDLINE | ID: mdl-32087024

ABSTRACT

BACKGROUND: POL7306 belongs to a new class of peptidomimetic outer-membrane-protein-targeting antibiotics with a novel mechanism of action. POL7306 is in development for the treatment of infections caused by antimicrobial-resistant Gram-negative bacteria and has demonstrated low cytotoxicity and nephrotoxicity. METHODS: A total of 891 isolates were collected by the SENTRY Antimicrobial Surveillance Program from 134 medical centres in Europe (n = 424; 41 centres in 18 nations), the USA (n = 411 isolates from 67 centres), the Asia-Pacific region (n = 24; 15 centres in 6 nations) and Latin America (n = 32; 11 centres in 9 nations) and included 558 Enterobacterales, 310 non-fermenters and 23 fastidious organisms. Susceptibility testing was performed using the reference broth microdilution method and the medium was supplemented with 0.002% polysorbate-80 for testing POL7306. Resistant subsets were characterized by WGS. RESULTS: POL7306 demonstrated potent in vitro activity against Enterobacterales [including carbapenem-resistant (MIC50/90, 0.06/0.25 mg/L), ESBL-producing (MIC50/90, 0.06/0.12 mg/L), KPC-producing (MIC50/90, 0.12/0.25 mg/L), MBL-producing (MIC50/90, 0.06/0.25 mg/L), colistin-non-susceptible, mcr-negative (MIC50/90, 0.5/2 mg/L) and mcr-positive (MIC50/90, 0.12/0.25 mg/L) Enterobacterales], Pseudomonas aeruginosa (MIC50/90, 0.25/0.25 mg/L), Acinetobacter baumannii (MIC50/90, 0.06/0.12 mg/L) and Stenotrophomonas maltophilia (MIC50/90, 0.06/0.25 mg/L). CONCLUSIONS: POL7306 demonstrated potent activity against a large collection of Gram-negative organisms collected worldwide that included colistin-resistant, XDR and ESBL- and carbapenemase-producing isolates for which there are currently limited treatment options.


Subject(s)
Drug Resistance, Multiple, Bacterial , Gram-Negative Bacteria , Anti-Bacterial Agents/pharmacology , Asia , Europe , Latin America , Microbial Sensitivity Tests
4.
J Med Chem ; 63(1): 88-102, 2020 01 09.
Article in English | MEDLINE | ID: mdl-31804829

ABSTRACT

LpxC inhibitors were optimized starting from lead compounds with limited efficacy and solubility and with the goal to provide new options for the treatment of serious infections caused by Gram-negative pathogens in hospital settings. To enable the development of an aqueous formulation for intravenous administration of the drug at high dose, improvements in both solubility and antibacterial activity in vivo were prioritized early on. This lead optimization program resulted in the discovery of compounds such as 13 and 30, which exhibited high solubility and potent efficacy against Gram-negative pathogens in animal infection models.


Subject(s)
Amidohydrolases/antagonists & inhibitors , Anti-Bacterial Agents/therapeutic use , Enzyme Inhibitors/therapeutic use , Escherichia coli Infections/drug therapy , Hydroxamic Acids/therapeutic use , Administration, Intravenous , Animals , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacokinetics , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Gram-Negative Bacteria/drug effects , Hepatocytes/metabolism , Hydroxamic Acids/administration & dosage , Hydroxamic Acids/chemical synthesis , Hydroxamic Acids/pharmacokinetics , Mice , Microbial Sensitivity Tests , Molecular Structure , Rats , Solubility
6.
Nature ; 576(7787): 452-458, 2019 12.
Article in English | MEDLINE | ID: mdl-31645764

ABSTRACT

There is an urgent need for new antibiotics against Gram-negative pathogens that are resistant to carbapenem and third-generation cephalosporins, against which antibiotics of last resort have lost most of their efficacy. Here we describe a class of synthetic antibiotics inspired by scaffolds derived from natural products. These chimeric antibiotics contain a ß-hairpin peptide macrocycle linked to the macrocycle found in the polymyxin and colistin family of natural products. They are bactericidal and have a mechanism of action that involves binding to both lipopolysaccharide and the main component (BamA) of the ß-barrel folding complex (BAM) that is required for the folding and insertion of ß-barrel proteins into the outer membrane of Gram-negative bacteria. Extensively optimized derivatives show potent activity against multidrug-resistant pathogens, including all of the Gram-negative members of the ESKAPE pathogens1. These derivatives also show favourable drug properties and overcome colistin resistance, both in vitro and in vivo. The lead candidate is currently in preclinical toxicology studies that-if successful-will allow progress into clinical studies that have the potential to address life-threatening infections by the Gram-negative pathogens, and thus to resolve a considerable unmet medical need.


Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Drug Resistance, Microbial , Gram-Negative Bacteria/drug effects , Peptidomimetics/chemistry , Peptidomimetics/pharmacology , Animals , Anti-Bacterial Agents/adverse effects , Bacterial Outer Membrane Proteins/chemistry , Bacterial Outer Membrane Proteins/genetics , Biological Products/chemistry , Drug Discovery , Drug Resistance, Microbial/drug effects , Escherichia coli Proteins/chemistry , Escherichia coli Proteins/genetics , Fluorescence , Gram-Negative Bacteria/genetics , Gram-Negative Bacteria/pathogenicity , Humans , Lipopolysaccharides/chemistry , Macrocyclic Compounds/adverse effects , Macrocyclic Compounds/chemistry , Macrocyclic Compounds/pharmacology , Male , Mice , Microbial Sensitivity Tests , Microbial Viability/drug effects , Microscopy, Electron, Transmission , Models, Molecular , Mutation , Peptidomimetics/adverse effects , Photoaffinity Labels
7.
Sci Rep ; 9(1): 5634, 2019 04 04.
Article in English | MEDLINE | ID: mdl-30948752

ABSTRACT

Oxazolidinones are synthetic antibiotics used for treatment of infections caused by Gram-positive bacteria. They target the bacterial protein synthesis machinery by binding to the peptidyl transferase centre (PTC) of the ribosome and interfering with the peptidyl transferase reaction. Cadazolid is the first member of quinoxolidinone antibiotics, which are characterized by combining the pharmacophores of oxazolidinones and fluoroquinolones, and it is evaluated for treatment of Clostridium difficile gastrointestinal infections that frequently occur in hospitalized patients. In vitro protein synthesis inhibition by cadazolid was shown in Escherichia coli and Staphylococcus aureus, including an isolate resistant against linezolid, the prototypical oxazolidinone antibiotic. To better understand the mechanism of inhibition, we determined a 3.0 Å cryo-electron microscopy structure of cadazolid bound to the E. coli ribosome in complex with mRNA and initiator tRNA. Here we show that cadazolid binds with its oxazolidinone moiety in a binding pocket in close vicinity of the PTC as observed previously for linezolid, and that it extends its unique fluoroquinolone moiety towards the A-site of the PTC. In this position, the drug inhibits protein synthesis by interfering with the binding of tRNA to the A-site, suggesting that its chemical features also can enable the inhibition of linezolid-resistant strains.


Subject(s)
Oxazolidinones/metabolism , Oxazolidinones/pharmacology , Protein Synthesis Inhibitors/pharmacology , Acetamides/pharmacology , Anti-Bacterial Agents/pharmacology , Clostridium Infections/drug therapy , Cryoelectron Microscopy/methods , Escherichia coli/metabolism , Fluoroquinolones/pharmacology , Humans , Microbial Sensitivity Tests , Peptidyl Transferases/antagonists & inhibitors , RNA, Transfer, Met/metabolism , Ribosomes/metabolism , Staphylococcus aureus/metabolism
8.
J Med Microbiol ; 67(9): 1402-1409, 2018 Sep.
Article in English | MEDLINE | ID: mdl-30052178

ABSTRACT

PURPOSE: Clostridium difficile infection (CDI) is an increasing cause of nosocomial diarrhoea worldwide, which has been partly attributed to the emergence of hypervirulent strains including C. difficile BI/NAP1/ribotype 027 and BK/NAP7/ribotype 078. Cadazolid is a new antibiotic currently in late-stage clinical studies for the treatment of CDI. The present study evaluated the in vitro bactericidal effect of cadazolid and comparator antibiotics against four C. difficile strains. The data demonstrate the potent and bactericidal activity of cadazolid against different ribotypes of C. difficile. METHODOLOGY: MICs for test antibiotics were determined in brain- heart infusion-supplemented broth (BHIS) containing 5 g l-1 yeast extract and 0.025 % (w/v) l-cysteine. Time-kill kinetics to investigate the rate of killing of each antibiotic at sub- and supra-MIC concentrations were performed at concentrations of 0.5, 1, 2, 4, 8 or 16× the MIC of cadazolid, vancomycin and fidaxomicin at intervals over a 48 h period.Results/key findings. Cadazolid-mediated killing of C. difficile was faster and occurred at lower concentrations than observed for vancomycin, while potency and killing was largely comparable to those observed for fidaxomicin. Notably, cadazolid also displayed a potent bactericidal effect against fluoroquinolone-resistant hypervirulent ribotype 027 and 078 strains. C. difficile spore formation was largely inhibited by all three antibiotics at concentrations >1× MIC; however, none were able to eliminate spores effectively, which were present at the start of the experiment. CONCLUSION: The data presented here demonstrate the potent in vitro bactericidal activity of cadazolid against different ribotypes of C. difficile, although on a limited set of strains.


Subject(s)
Anti-Bacterial Agents/pharmacology , Clostridioides difficile/drug effects , Oxazolidinones/pharmacology , Aminoglycosides/pharmacology , Clostridioides difficile/chemistry , Clostridioides difficile/classification , Clostridioides difficile/growth & development , Clostridium Infections/microbiology , Fidaxomicin , Humans , Kinetics , Microbial Sensitivity Tests , Ribotyping , Vancomycin/pharmacology
9.
Article in English | MEDLINE | ID: mdl-28584149

ABSTRACT

Cadazolid (CDZ) is a new antibiotic currently in clinical development for the treatment of Clostridium difficile infections. CDZ interferes with the bacterial protein synthesis machinery. The aim of the present study was to identify resistance mechanisms for CDZ and compare the results to those obtained for linezolid (LZD) in C. difficile by whole-genome sequencing (WGS) of strains generated by in vitro passages and to those obtained for LZD-resistant clinical isolates. Clones of C. difficile 630 selected with CDZ during 46 passages had a maximally 4-fold increase in CDZ MIC, while the LZD MIC for clones selected with LZD increased up to 16-fold. CDZ cross-resistance with LZD was maximally 4-fold, and no cross-resistance with other antibiotics tested was observed. Our data suggest that there are different resistance mechanisms for CDZ and LZD in C. difficile Mutations after passages with CDZ were found in rplD (ribosomal protein L4) as well as in tra and rmt, whereas similar experiments with LZD showed mutations in rplC (ribosomal protein L3), reg, and tpr, indicating different resistance mechanisms. Although high degrees of variation between the sequenced genomes of the clinical isolates were observed, the same mutation in rplC was found in two clinical isolates with high LZD MICs. No mutations were found in the 23S rRNA genes, and attempts to isolate the cfr gene from resistant clinical isolates were unsuccessful. Analysis of 50% inhibitory concentrations (IC50s) determined in in vitro transcription/translation assays performed with C. difficile cell extracts from passaged clones correlated well with the MIC values for all antibiotics tested, indicating that the ribosomal mutations are causing the resistant phenotype.


Subject(s)
Anti-Bacterial Agents/pharmacology , Clostridioides difficile/drug effects , Clostridioides difficile/genetics , Drug Resistance, Bacterial/genetics , Linezolid/pharmacology , Oxazolidinones/pharmacology , Protein Synthesis Inhibitors/pharmacology , Ribosomal Proteins/genetics , Amino Acid Sequence , Clostridioides difficile/isolation & purification , Drug Resistance, Bacterial/physiology , Genome, Bacterial/genetics , Humans , Microbial Sensitivity Tests , RNA, Ribosomal, 23S/genetics , Ribosomal Protein L3 , Sequence Analysis, DNA
10.
J Med Chem ; 60(9): 3776-3794, 2017 05 11.
Article in English | MEDLINE | ID: mdl-28406300

ABSTRACT

There is an urgent unmet medical need for novel antibiotics that are effective against a broad range of bacterial species, especially multidrug resistant ones. Tetrahydropyran-based inhibitors of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) display potent activity against Gram-positive pathogens and no target-mediated cross-resistance with fluoroquinolones. We report our research efforts aimed at expanding the antibacterial spectrum of this class of molecules toward difficult-to-treat Gram-negative pathogens. Physicochemical properties (polarity and basicity) were considered to guide the design process. Dibasic tetrahydropyran-based compounds such as 6 and 21 are potent inhibitors of both DNA gyrase and topoisomerase IV, displaying antibacterial activities against Gram-positive and Gram-negative pathogens (Staphylococcus aureus, Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii). Compounds 6 and 21 are efficacious in clinically relevant murine infection models.


Subject(s)
Anti-Bacterial Agents/pharmacology , Gram-Negative Bacteria/drug effects , Pyrans/pharmacology , Topoisomerase Inhibitors/chemical synthesis , Topoisomerase Inhibitors/pharmacology , Animals , Anti-Bacterial Agents/adverse effects , Anti-Bacterial Agents/chemical synthesis , Guinea Pigs , Humans , Microbial Sensitivity Tests , Myocytes, Cardiac/drug effects , Pyrans/adverse effects , Pyrans/chemical synthesis , Topoisomerase Inhibitors/adverse effects
11.
Antimicrob Agents Chemother ; 60(1): 628-31, 2016 01.
Article in English | MEDLINE | ID: mdl-26503650

ABSTRACT

The promotion of colonization with vancomycin-resistant enterococci (VRE) is one potential side effect during treatment of Clostridium difficile-associated diarrhea (CDAD), resulting from disturbances in gut microbiota. Cadazolid (CDZ) is an investigational antibiotic with potent in vitro activity against C. difficile and against VRE and is currently in clinical development for the treatment of CDAD. We report that CDZ treatment did not lead to intestinal VRE overgrowth in mice.


Subject(s)
Anti-Bacterial Agents/adverse effects , Clostridioides difficile/drug effects , Diarrhea/drug therapy , Enterocolitis, Pseudomembranous/drug therapy , Oxazolidinones/pharmacology , Vancomycin/adverse effects , Aminoglycosides/pharmacology , Animals , Anti-Bacterial Agents/administration & dosage , Clostridioides difficile/growth & development , Clostridioides difficile/pathogenicity , Colony Count, Microbial , Diarrhea/etiology , Diarrhea/microbiology , Diarrhea/pathology , Enterocolitis, Pseudomembranous/etiology , Enterocolitis, Pseudomembranous/microbiology , Enterocolitis, Pseudomembranous/pathology , Fidaxomicin , Intestines/drug effects , Intestines/microbiology , Intestines/pathology , Metronidazole/pharmacology , Mice , Microbial Sensitivity Tests , Streptococcal Infections/drug therapy , Streptococcal Infections/microbiology , Streptococcal Infections/pathology , Treatment Outcome , Vancomycin/administration & dosage , Vancomycin Resistance , Vancomycin-Resistant Enterococci/drug effects , Vancomycin-Resistant Enterococci/growth & development , Vancomycin-Resistant Enterococci/pathogenicity
12.
Antimicrob Agents Chemother ; 58(2): 892-900, 2014.
Article in English | MEDLINE | ID: mdl-24277020

ABSTRACT

Clostridium difficile is a leading cause of health care-associated diarrhea with significant morbidity and mortality, and new options for the treatment of C. difficile-associated diarrhea (CDAD) are needed. Cadazolid is a new oxazolidinone-type antibiotic that is currently in clinical development for treatment of CDAD. Here, we report the in vitro and in vivo antibacterial evaluation of cadazolid against C. difficile. Cadazolid showed potent in vitro activity against C. difficile with a MIC range of 0.125 to 0.5 µg/ml, including strains resistant to linezolid and fluoroquinolones. In time-kill kinetics experiments, cadazolid showed a bactericidal effect against C. difficile isolates, with >99.9% killing in 24 h, and was more bactericidal than vancomycin. In contrast to metronidazole and vancomycin, cadazolid strongly inhibited de novo toxin A and B formation in stationary-phase cultures of toxigenic C. difficile. Cadazolid also inhibited C. difficile spore formation substantially at growth-inhibitory concentrations. In the hamster and mouse models for CDAD, cadazolid was active, conferring full protection from diarrhea and death with a potency similar to that of vancomycin. These findings support further investigations of cadazolid for the treatment of CDAD.


Subject(s)
Anti-Bacterial Agents/pharmacology , Clostridioides difficile/drug effects , Clostridium Infections/drug therapy , Enterocolitis, Pseudomembranous/drug therapy , Oxazolidinones/pharmacology , Spores, Bacterial/drug effects , Acetamides/pharmacology , Animals , Bacterial Proteins/antagonists & inhibitors , Bacterial Proteins/biosynthesis , Bacterial Toxins/antagonists & inhibitors , Bacterial Toxins/biosynthesis , Clostridioides difficile/growth & development , Clostridioides difficile/metabolism , Clostridium Infections/microbiology , Clostridium Infections/mortality , Cricetinae , Enterocolitis, Pseudomembranous/microbiology , Enterocolitis, Pseudomembranous/mortality , Enterotoxins/antagonists & inhibitors , Enterotoxins/biosynthesis , Female , Fluoroquinolones/pharmacology , Humans , Linezolid , Male , Metronidazole/pharmacology , Mice , Mice, Inbred C57BL , Microbial Sensitivity Tests , Spores, Bacterial/growth & development , Survival Analysis , Vancomycin/pharmacology
13.
Antimicrob Agents Chemother ; 58(2): 901-8, 2014.
Article in English | MEDLINE | ID: mdl-24277035

ABSTRACT

Cadazolid is a new oxazolidinone-type antibiotic currently in clinical development for the treatment of Clostridium difficile-associated diarrhea. Here, we report investigations on the mode of action and the propensity for spontaneous resistance development in C. difficile strains. Macromolecular labeling experiments indicated that cadazolid acts as a potent inhibitor of protein synthesis, while inhibition of DNA synthesis was also observed, albeit only at substantially higher concentrations of the drug. Strong inhibition of protein synthesis was also obtained in strains resistant to linezolid, in agreement with low MICs against such strains. Inhibition of protein synthesis was confirmed in coupled transcription/translation assays using extracts from different C. difficile strains, including strains resistant to linezolid, while inhibitory effects in DNA topoisomerase assays were weak or not detectable under the assay conditions. Spontaneous resistance frequencies of cadazolid were low in all strains tested (generally <10(-10) at 2× to 4× the MIC), and in multiple-passage experiments (up to 13 passages) MICs did not significantly increase. Furthermore, no cross-resistance was observed, as cadazolid retained potent activity against strains resistant or nonsusceptible to linezolid, fluoroquinolones, and the new antibiotic fidaxomicin. In conclusion, the data presented here indicate that cadazolid acts primarily by inhibition of protein synthesis, with weak inhibition of DNA synthesis as a potential second mode of action, and suggest a low potential for spontaneous resistance development.


Subject(s)
Anti-Bacterial Agents/pharmacology , Clostridioides difficile/drug effects , Drug Resistance, Bacterial/genetics , Protein Biosynthesis/drug effects , Acetamides/pharmacology , Aminoglycosides/pharmacology , Clostridioides difficile/genetics , Clostridioides difficile/growth & development , Clostridioides difficile/metabolism , DNA Gyrase/genetics , DNA Gyrase/metabolism , Drug Resistance, Bacterial/drug effects , Fidaxomicin , Fluoroquinolones/pharmacology , Linezolid , Microbial Sensitivity Tests , Oxazolidinones/pharmacology , Protein Biosynthesis/genetics , RNA/antagonists & inhibitors , RNA/biosynthesis , Recombinant Proteins , Subcellular Fractions/chemistry , Subcellular Fractions/metabolism , Transcription, Genetic/drug effects , Vancomycin/pharmacology
14.
Chemotherapy ; 56(4): 318-24, 2010.
Article in English | MEDLINE | ID: mdl-20714150

ABSTRACT

OBJECTIVES: In this study, the in vitro antimicrobial activity and spectrum of new dimeric compounds derived from the cyanobacterial alkaloid nostocarboline were investigated. The mechanism of action and selectivity to bacteria were studied and compared to the cationic antiseptic chlorhexidine. METHODS: Minimal inhibitory concentrations were determined against clinical isolates and against a panel of microbial reference strains using the CLSI microdilution method. Bacterial membrane damage was addressed by measuring ATP leakage and the mode of action was investigated in Escherichia coli reporter strains. Selectivity was tested by a cytotoxicity assay using MTS. RESULTS: The antimicrobial potency of dimers varied with length of the hydrophobic linker. The most potent compounds, NCD9 and NCD10, had a C10 and C12 linker, respectively, and showed strong activity against Gram-positive bacteria, notably methicillin-resistant Staphylococcus aureus strains. Similar to chlorhexidine, these compounds showed a rapid concentration-dependent bactericidal effect, which correlated with membrane damage as indicated by ATP leakage. NCD9, in contrast to NCD10 and chlorhexidine, lacked activity against yeast strains and showed low cytotoxicity in CHO cells indicating a high degree of selectivity. In E. coli reporter strains, NCD9 induced the DegP response pathway as well as the SOS response, suggesting interaction with both the cell envelope and DNA metabolism. CONCLUSIONS: The results presented in this report indicate the potential of this new class of cationic antimicrobial compounds for the design of potent and selective antibacterials with low cytotoxicity.


Subject(s)
Alkaloids/pharmacology , Anti-Infective Agents, Local/pharmacology , Carbolines/pharmacology , Chlorhexidine/pharmacology , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Animals , Anti-Bacterial Agents/pharmacology , CHO Cells , Carbolines/chemistry , Ciprofloxacin/pharmacology , Ciprofloxacin/therapeutic use , Cricetinae , Cricetulus , Dimerization , Escherichia coli/drug effects , Methicillin-Resistant Staphylococcus aureus/drug effects , Microbial Sensitivity Tests
15.
Curr Pharm Des ; 13(30): 3140-54, 2007.
Article in English | MEDLINE | ID: mdl-17979755

ABSTRACT

Based on the mode of action of antibacterial drugs currently used, targets can be defined as distinct cellular constituents such as enzymes, enzyme substrates, RNA, DNA, and membranes which exhibit very specific binding sites at the surface of these components or at the interface of macromolecular complexes assembled in the cell. Intriguingly, growth inhibition or even complete loss of bacterial viability is often the result of a cascade of events elicited upon treatment with an antibacterial agent. In addition, their mode of action frequently involves more than one single target. A comprehensive description of the targets exploited so far by commercialized antibacterial agents, including anti-mycobacterial agents, is given. The number of targets exploited so far by commercial antibacterial agents is estimated to be about 40. The most important biosynthetic pathways and cellular structures affected by antibacterial drugs are the cell wall biosynthesis, protein biosynthesis, DNA per se, replication, RNA per se, transcription and the folate biosynthetic pathway. The disillusionment with the genomics driven antibacterial drug discovery is a result of the restrictive definition of targets as products of essential and conserved genes. Emphasis is made to not only focus on proteins as potential drug targets, but increase efforts and devise screening technologies to discover new agents interacting with different RNA species, DNA, new protein families or macromolecular complexes of these constituents.


Subject(s)
Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Bacteria/genetics , Bacteria/metabolism , Drug Design , Genome, Bacterial , Humans
16.
J Org Chem ; 72(22): 8361-70, 2007 Oct 26.
Article in English | MEDLINE | ID: mdl-17902695

ABSTRACT

The first biomimetic total synthesis of the iron chelator anachelin H isolated from the cyanobacterium Anabaena cylindrica is reported. A first generation approach delivered one enantiomeric series of the polyketide fragment. Comparison of the 1H NMR data suggested the relative configuration of this anachelin fragment. The relative and absolute configuration of anachelin H was then established by total synthesis. A second generation approach involved the enzymatic conversion of N,N-dimethyltyramine to the anachelin chromophore. It was demonstrated that the enzyme tyrosinase is activated by the product during this reaction, the anachelin chromophore can serve as a tyrosinase activator. Anachelin H was evaluated against a panel of eleven bacterial and fungal pathogens, and moderate antibiotic activity (32 microg/mL) against Moraxella catarrhalis was found.


Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Antifungal Agents/chemical synthesis , Antifungal Agents/pharmacology , Moraxella catarrhalis/drug effects , Oligopeptides/chemical synthesis , Oligopeptides/pharmacology , Quinolinium Compounds/chemical synthesis , Quinolinium Compounds/pharmacology , Saccharomyces cerevisiae/drug effects , Anabaena cylindrica/chemistry , Anti-Bacterial Agents/chemistry , Antifungal Agents/chemistry , Biomimetics , Microbial Sensitivity Tests , Molecular Conformation , Oligopeptides/chemistry , Quinolinium Compounds/chemistry , Stereoisomerism
17.
Org Lett ; 8(4): 737-40, 2006 Feb 16.
Article in English | MEDLINE | ID: mdl-16468755

ABSTRACT

[structure: see text] Nostocarboline and seven derivatives were prepared and displayed minimal inhibitory concentration (MIC) values >or=100 nM against the growth of Microcystis aeruginosa PCC 7806, Synechococcus PCC 6911, and Kirchneriella contorta SAG 11.81, probably via the inhibition of photosynthesis. The natural product hybrid nostocarboline/ciprofloxacin displayed additional antibacterial activity against several Gram-negative bacteria (MICs >or=0.7 microM). Nostocarboline can thus be considered a potent, selective, readily available, natural algicide.


Subject(s)
Alkaloids , Anti-Infective Agents , Bacteria/drug effects , Carbolines , Chlorophyta/drug effects , Microcystis/drug effects , Synechococcus/drug effects , Alkaloids/chemical synthesis , Alkaloids/chemistry , Alkaloids/pharmacology , Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/chemistry , Anti-Infective Agents/pharmacology , Carbolines/chemical synthesis , Carbolines/chemistry , Carbolines/pharmacology , Microbial Sensitivity Tests , Molecular Structure
18.
Bioorg Med Chem Lett ; 13(23): 4229-33, 2003 Dec 01.
Article in English | MEDLINE | ID: mdl-14623007

ABSTRACT

Oxazolidinone-quinolone hybrids, which combine the pharmacophores of a quinolone and an oxazolidinone, were synthesised and shown to be active against a variety of susceptible and resistant Gram-positive and Gram-negative bacteria. The nature of the spacer greatly influences the antibacterial activity by directing the mode of action, that is quinolone- and/or oxazolidinone-like activity. The best compounds in this series have a balanced dual mode of action and overcome all types of resistance, including resistance to quinolones and linezolid, in clinically relevant Gram-positive pathogens.


Subject(s)
Anti-Bacterial Agents/pharmacology , Drug Resistance, Bacterial , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Oxazolidinones/pharmacology , Quinolones/pharmacology , Acetamides/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , DNA Topoisomerase IV/antagonists & inhibitors , Linezolid , Microbial Sensitivity Tests , Molecular Structure , Oxazolidinones/chemical synthesis , Oxazolidinones/chemistry , Quinolones/chemical synthesis , Quinolones/chemistry , Structure-Activity Relationship
19.
Bioorg Med Chem ; 11(10): 2313-9, 2003 May 15.
Article in English | MEDLINE | ID: mdl-12713843

ABSTRACT

Oxazolidinone-quinolone hybrids that combine the pharmacophores of a quinolone and an oxazolidinone were synthesised and shown to be active against a variety of resistant and susceptible Gram-positive and fastidious Gram-negative organisms. The best compounds in this series overcome all types of resistance in relevant clinical Gram-positive pathogens. The nature of the spacer greatly influences the antibacterial activity. The dual mode of action could be demonstrated for compounds having a piperazinyl spacer. Antibacterial activity was higher at acidic pH.


Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Oxazolidinones/chemistry , Oxazolidinones/pharmacology , Quinolones/chemistry , Quinolones/pharmacology , Anti-Bacterial Agents/chemical synthesis , DNA Gyrase/metabolism , DNA Topoisomerase IV/metabolism , Drug Design , Drug Evaluation, Preclinical , Drug Resistance, Multiple , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Microbial Sensitivity Tests , Molecular Structure , Oxazolidinones/chemical synthesis , Protein Biosynthesis , Quinolones/chemical synthesis , Structure-Activity Relationship , Transcription, Genetic
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