Nafsika H Georgopapadakou

• PhD, Yale University
• NHG Consulting, Anti-infectives & Oncology, Princeton, NJ, USA

Ketolides are erythromycin A derivatives with a keto group replacing the cladinose sugar and an aryl-alkyl group attached to the lactone macrocycle. The aryl-alkyl extension broadens its antibacterial spectrum to include all pathogens responsible for community-acquired pneumonia (CAP): Streptococcus pneumoniae, Haemophilus influenzae, Moraxella cat...

The present invention relates to compositions and methods to selectively treat fungal infection. More particularly, this invention relates to compositions and methods for selectively enhancing fungal sensitivity to antifungal compounds.

Bacterial resistance to antibacterial drugs has been increasing relentlessly over the past two decades. This includes common residents of the human body: Staphylococcus aureus (methicillin resistant or MRSA) Enteroccus faecalis and E. faecium (vancomycin resistant or VRE): Enterobacteriaceae (multiresistant, carbapenems included or CRE). It also in...

This invention provides novel β-lactamase inhibitors of the aryl- and heteroaryl-sulfonamidomethylphosphonate monoester class having nitrogen-based cations or quarternary ammomium groups. The compounds inhibit three classes of β-lactamases and synergize the antibacterial effects of β-lactam antibiotics (e.g., imipenem and ceftazimdime) against thos...

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis and the biological evaluation of ammonium ion analogues of the first carbocyclic cationic intermediate 4 presumed to formed during the cyclization of 2,3-oxidosqualene to protesterol, 2, by 2,3-oxidosqualene-lanosterol cyclase (OSC) is presented. Preparation of the required 4-hydroxy-2,3-substituted-4-piperidine 12 (and its corresponding...

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

We report on the in vitro activity of the Hos2 fungal histone deacetylase (HDAC) inhibitor MGCD290 (MethylGene, Inc.) in combination with azoles against azole-resistant yeasts and molds. Susceptibility testing was performed by the CLSI M27-A3 and M38-A2 broth microdilution methods. Testing of the combinations (MGCD290 in combination with fluconazol...

2-Dichloroamino-2-methyl-propane-1-sulfonic acid sodium salt (2a), a stable derivative of endogenous N,N-dichlorotaurine (1), has been identified and is under development as a topical antimicrobial agent. Structure-activity relationships of analogs were explored to achieve optimal antimicrobial activity with minimal mammalian toxicity while maintai...

Background: N,N-dichloro-2,2-dimethyltaurine (NVC-422) is a stable derivative of N-chlorotaurine with potent activity against gram-positive and gram-negative bacteria and yeasts. The present study was aimed at determining the potential for spontaneous resistance to NVC-422 and for cross-resistance with clinically used antibiotics. Methods: MBCs for...

The Annual Meeting of the American Association for Cancer Research (AACR) brings together research in fundamental biology, translational science, drug development and clinical testing of emerging anticancer therapies. Among the highlights of the 2007 Annual Meeting were major research themes on drug action, drug resistance and new drug development....

This perspective is the fifth in a series discussing drugs dropped from development in 2005, of which 11 were being developed for infectious diseases. Of these, eight were antivirals and were dropped in Phase II or III: Medivir's alovudine, Ono Pharmaceuticals' aplaviroc hydrochloride and Excite's immunotherapeutic Xcellerate for HIV; Boehringer In...

Widespread resistance to our arsenal of antibiotics is no longer a threat - it is reality. With no new antibacterial drugs expected to reach the market any time soon, immediate action is needed to avert a looming healthcare disaster. But antibacterial discovery faces immense scientific and business challenges. What needs to be done to turn the tide...

The annual meeting of the American Association for Cancer Research (AACR) provided a panoramic view of new developments and trends in cancer research. In the area of new drug development, a recurrent theme was receptor tyrosine kinase (TK) inhibitors, with multi-targeted, small molecule inhibitors - highly potent against a family of receptors such...

Biofilms are microbial communities encased in polysaccharide-rich extracellular matrices and living in association with surfaces (1). Biofilm formation is an important process for survival of microbial pathogens in the environment (e.g., Vibrio cholerae) or in the mammalian host (e.g., Pseudomonas aeruginosa). Free-swimming (planktonic) microbial c...

The many and diverse beta-lactamases produced by bacteria, particularly by Gram-negative pathogens, are increasingly posing a serious threat to the clinical utility of beta-lactams. First-generation inhibitors (clavulanic acid, sulbactam, tazobactam) focus on Ambler class A enzymes. However, recent structural upgrades of class A beta-lactamases (e....

The International Conference on Molecular Targets and Therapeutics, jointly sponsored by the American Association for Cancer Research (AACR), National Cancer Institute (NCI) and European Organization for Research and Treatment of Cancer (EORTC), was held in Boston on November 17-21, 2003. It offered updates of the latest developments and emerging t...

Two potent antibacterial agents designed to undergo enzyme-catalyzed therapeutic activation were evaluated for their mechanisms of action. The compounds, NB2001 and NB2030, contain a cephalosporin with a thienyl (NB2001) or a tetrazole (NB2030) ring at the C-7 position and are linked to the antibacterial triclosan at the C-3 position. The compounds...

The 41st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) was held in Chicago on 16-19 December 2001, rescheduled following the tragic events of 11th September. Nonetheless, it attracted thousands of delegates from industry and academia and covered, in over 2200 oral and poster presentations, topics ranging from bioterrorism...

Invasive fungal infections have increased dramatically in recent years to become important causes of morbidity and mortality in hospitalised patients. Currently available antifungal drugs for such infections essentially have three molecular targets: 14 alpha demethylase (azoles), ergosterol (polyenes) and beta-1,3-glucan synthase (echinocandins). T...

The development of new anticancer drugs and the identification of novel targets represent major focus areas for pharmaceutical and biotech companies, universities and research institutes worldwide. The 92nd Annual Meeting of the American Association for Cancer Research (AACR) provided a glimpse of the latest developments in the cancer field. We hig...

Currently available antifungal drugs for serious infections are either fungistatic and vulnerable to resistance (azoles) or fungicidal but toxic to the host (polyenes). Cell wall-acting antifungals are inherently selective and fungicidal, features that make them particularly attractive for clinical development. Three classes of such compounds, targ...

40th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) was held in Toronto on 17-20 September 2000. It attracted thousands of delegates from industry and academia and covered, in over 2300 oral and poster presentations, topics ranging from microbial pathogenesis to infection control, vaccines, antibiotic resistance and new an...

Currently available antifungal drugs for serious infections have essentially two molecular targets, 14alpha demethylase (azoles) and ergosterol (polyenes). The former is a fungistatic target, vulnerable to resistance development; the latter, while a fungicidal target, is not sufficiently different from the host to ensure high selectivity. Antifunga...

The 91st Annual Meeting of the American Association for Cancer Research (AACR) provided the latest developments in cancer research. We highlight here presentations on resistance mechanisms (tumor microenvironment, efflux pumps, apoptosis), new targets and drugs in development (signal transduction, cell cycle, apoptosis, microtubules, topoisomerases...

Inositol phosphorylceramide (IPC) synthase is an enzyme common to fungi and plants that catalyzes the transfer of phosphoinositol from phosphatidylinositol to ceramide to form IPC. The reaction is a key step in fungal sphingolipid biosynthesis and the target of the antibiotics galbonolide A, aureobasidin A, and khafrefungin. As a first step toward...

A novel peptide termed XMP-445 based on the bactericidal/permeability-increasing protein (BPI) and having antifungal and antibacterial activity is claimed. The protein is related to peptides derived or based upon domain III of the mammalian BPI protein isolated from the granules of polymorphonuclear leukocytes. The peptide is claimed for use to tre...

Inositol phosphorylceramide synthase (IPC synthase) is an essential and unique enzyme in fungal sphingolipid biosynthesis and is the target of the cyclic nonadepsipeptide antibiotic aureobasidin A. As a first step towards understanding the mechanism of aureobasidin A inhibition, we developed a fluorometric HPLC assay for IPC synthase using the Sacc...

This report focuses on the symposia related to fungal diagnostics, pathogenesis and antifungal chemotherapy, with emphasis on new developments of established agents and new agents in preclinical and clinical development.

The renaissance in infections diseases, stimulated by well-documented and publicized microbial resistance, continues. The field is benefiting from the infusion of new technologies, aimed at accelerating the discovery process: genomics, combinatorial chemistry and high throughput screening. At this year's ICAAC, there were numerous reports on drug r...

Serious fungal infections, caused mostly by opportunistic species, are increasingly common in immunocompromised and other vulnerable patients. The use of antifungal drugs, primarily azoles and polyenes, has increased in parallel. Yet, established agents do not satisfy the medical need completely: azoles are fungistatic and vulnerable to resistance,...

Renewed public awareness of infectious diseases, the commercial success of marketed antimicrobial agents and the well-publicized microbial resistance to them, have greatly stimulated infectious disease research in the pharmaceutical and biotechnology industry and this was reflected in the conference. In the antibacterial field, there were useful up...

Serious fungal infections are increasingly common in immunocompromised patients and existing antifungals do not completely satisfy the medical need. The latter have either considerable toxicity, e.g., amphotericin, which is, however, less toxic in lipid formulations, or have limited activity, e.g., azoles. Cell wall acting antifungals are inherentl...

Microsomal and soluble peptidases from bovine liver and pig brain hydrolyze the farnesylated, Ras-based CAAX peptide [3H]Ac-fCVIM-OH. However, they differ in their sensitivity to substrate-based inhibitors, sulfhydryl and chelating agents, pH and ionic strength optima, and stability. The microsomal activity was exquisitely sensitive to the substrat...

Four analogs of the carboxy terminus of unprocessed p21Ras protein were evaluated as inhibitors of the p21Ras processing farnesyltransferase and peptidase. While three showed no crossover of inhibitory activity between the enzymes, the fourth (a naphthyl-substituted peptide) inhibited both farnesyltransferase and peptidase, with IC50s of 16 microM...

Fungal infections are increasingly common and, in certain vulnerable patients, can be serious and even life threatening. The fungal cell wall, a structure with no mammalian counterpart, presents an attractive therapeutic target. Inhibitors of the synthesis of one cell-wall component, beta-(1,3)-glucan, are currently under development as antifungal...

Four spontaneous, single-step mutants of Escherichia coli K-12 resistant to low levels of the cephalosporin 3'-quinolone ester Ro 23-9424 were isolated at a frequency of 10(-10) to 10(-11) mutants per CFU plated. The mutants were cross-resistant to both cephalosporin (cefotaxime) and quinolone (fleroxacin) components. Accordingly, they had altered...

2,3-Oxidosqualene (23-OS) analogs that contain thioether (52-55) and sulfoxide (56-60) at positions normally occupied by carbons considered to be cationic during 2,3-oxidosqualene-lanosterol cyclase (OSC) cyclization (C-6, C-10, C-14, and C-19) were synthesized and tested as substrate mimic inhibitors of fungal and mammalian OSC. The analogs were f...

A simple and sensitive radiometric assay for the peptidase involved in the post-translational processing of p21ras proteins at the carboxy-terminal Cys-aliphatic-aliphatic--any amino acid (CAAX) motif is described. An isoprenylated tetrapeptide substrate, N-acetyl-S-[3H]farnesyl-Cys-Val-Ile-Ser-OH (22-27 Ci/mmol), was synthesized from N-acetyl-Cys-...

The beta-lactam hydrolysis of five cephalosporin 3'-quinolones (dual-action cephalosporins) by three gram-negative beta-lactamases was examined. The dual-action cephalosporins tested were the ester Ro 23-9424; the carbamates Ro 25-2016, Ro 25-4095, and Ro 25-4835; and the tertiary amine Ro 25-0534. Also tested were cephalosporins with similar side...

We have previously reported that linking quinolones to the cephalosporin 3'-position through an ester bond, a carbamate function, or a bond through a quaternary nitrogen produced cephalosporins with a dual mode of antibacterial action. We now describe a new class of dual-action cephalosporins, with greater chemical stability than those previously r...

A series of 6-aminoacyl penams were prepared in order to simulate the D-ala-D-ala-OH portion of the donor muramyl peptide involved in the transpeptidation reaction during the formation of the bacterial cell wall. (R)-, and (S)-4-Aminoacyl-α-butyl α-benzyl penicillins were prepared as models, and their binding to PBPs was studied.

The lipopolysaccharide and porin profile of Escherichia coli ATCC 25922, a smooth strain commonly used in antibiotic susceptibility testing, and five isogenic rough mutants was examined. The lipopolysaccharide of the parent strain had the characteristic ladder pattern on polyacrylamide gels, while that of the mutants appeared similar to chemotypes...

Cephalosporin 3'-quinolone esters, carbamates, and tertiary amines are potent antibiotics whose antibacterial activities reflect the action of both the beta-lactam and the quinolone components. The biological properties of representative compounds from each class were compared in Escherichia coli. All compounds bound to the essential PBP 3, inhibit...

The lipopolysaccharide and porin profile of Escherichia coli ATCC 25922, a smooth strain commonly used in antibiotic susceptibility testing, and five isogenic rough mutants was examined. The lipopolysaccharide of the parent strain had the characteristic ladder pattern on polyacrylamide gels, while that of the mutants appeared similar to chemotypes...

Synthesis and the biological evaluation of ammonium ion analogues of the first carbocyclic cationic intermediate 4 presumed to formed during the cyclization of 2,3-oxidosqualene to protosterol, 2, by 2,3-oxidisqualene-lanosterol cyclase (OSC) is presented. Preparation of the required 4-hydroxy-2,3-substituted-4-piperidine 12 (and its corresponding...

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The accumulation of quinolones by Escherichia coli JF568, Pseudomonas aeruginosa PAO1, and Staphylococcus aureus ATCC 29213 was measured by a modified fluorometric assay (J. S. Chapman and N. H. Georgopapadakou, Antimicrob. Agents Chemother. 33:27-29, 1989). The quinolones examined were fleroxacin, pefloxacin, norfloxacin, difloxacin, A56620, cipro...

The relationship between sterol biosynthesis inhibition, membrane integrity, and cell growth inhibition in Candida albicans was examined for five squalene epoxidase inhibitors. The compounds were the thiocarbamates tolnaftate and tolciclate and the allylamines naftifine, terbinafine, and SDZ 87-469. All compounds inhibited sterol biosynthesis, with...

Two new series of dual-action antibacterial agents were synthesized in which penems and carbapenems were linked at the 2'-position to quinolones through either an ester or a carbamate moiety. Potent, broad-spectrum antibacterial activity was observed for both classes of compounds, indicative of a dual-mode of action.

The effects of quinolone antibiotics on nucleoid segregation in growing Escherichia coli were examined by using fleroxacin (Ro 23-6240, AM 833) as a prototype compound. At levels that were close to its MIC and induced growth arrest and filamentation, fleroxacin caused large nucleoids to appear in midcell, suggesting inhibition of nucleoid segregati...

The fungal cell wall is a major and essential fungal structure, entirely lacking in animal cells, and thus an attractive chemotherapeutic target. Its biosynthesis is central to cell division and morphogenesis. Like its bacterial counterpart, the fungal cell wall determines cell shape, provides rigidity and osmotic support, and plays an important ro...

It has been 50 years since Florey, Chain and their associates first described the treatment of staphylococcal and streptococcal infections with penicillin (49). This epoch-making discovery ushered in a new era of fruitful research culminating in the identification of the bacterial cell wall as the target of this β-lactam (222). Penicillin was found...

Emerging Targets in Antibacterial and Antifungal Chemotherapy offers constructive ideas to researchers that could lead to the discovery of entirely new classes of drugs. The authors emphasize new topics rather than review work on known antibacterials and antifungals, and identify new targets--either the rate-limiting component of a biochemical path...

In a previous study (C. C. Hall, J. D. Watkins, and N. H. Georgopapadakou, Antimicrob. Agents Chemother. 33:322-325, 1989), the elongation factor Tu (EF-Tu) from Staphylococcus aureus was found to be insensitive to a series of kirromycin analogs which were inhibitory to the EF-Tu from Escherichia coli. In the present study, the EF-Tu from S. aureus...

A series of cephalosporins has been prepared in which the 3'-position was linked to the nitrogen of the antibacterial quinolone ciprofloxacin through a carbamate function. Like the ester-linked and quaternary-linked dual-action cephalosporins reported earlier, these carbamate-linked compounds exhibited a broad antibacterial spectrum derived from bo...

Ro 23-9424 is a broad-spectrum antibacterial agent consisting of a cephalosporin (desacetylcefotaxime) linked through an ester bond to a fluoroquinolone (fleroxacin). Its activity against mutants of Escherichia coli TE18 resistant to both antibacterial components was examined. E. coli TE18 overproduces the AmpC beta-lactamase and is resistant to se...

When cephalosporins exert their biological activity by reacting with bacterial enzymes, opening of the beta-lactam ring can lead to expulsion of the 3'-substituent. A series of cephalosporins was prepared in which antibacterial quinolones were linked to the 3'-position through a quaternary nitrogen. Like the 3'-ester-linked dual-action cephalospori...

According to the generally accepted mechanism by which bacterial enzymes react with cephalosporins, opening of the beta-lactam ring can lead to the expulsion of a 3'-substituent. A series of dual-action cephalosporins was prepared in which antibacterial quinolones were linked to the cephalosporin 3'-position through an ester bond in the expectation...

Ro 23-9424 is a broad-spectrum antibacterial agent composed of a cephalosporin and a quinolone moiety. Its biological properties were compared with those of its two components and structurally related cephalosporins and quinolones. Like ceftriaxone and cefotaxime but unlike its decomposition product, desacetyl cefotaxime, Ro 23-9424 bound at less t...

Ro 23-9424 represents the culmination of an idea put forth by O'Callaghan et al4 in 1976. They proposed that a cephalosporin could act as a carrier for a second antibacterial with the total molecule functioning as a single antibacterial until separated by opening of the ß-lactam ring by a ß-lactamase or, as we now know, the target penicillin-sensit...

Six kirromycin analogs (elfamycins) were compared on the basis of their inhibition of Escherichia coli poly(U)-directed poly(Phe) synthesis and stimulation of elongation factor Tu (EF-Tu)-associated GTPase activity. The elfamycins tested were kirromycin, aurodox, efrotomycin, phenelfamycin A, unphenelfamycin, and L-681,217. The last three lack the...

Spontaneous fleroxacin-resistant mutants of Escherichia coli K-12 were isolated at a frequency of 10(-10) to 10(-11) mutants per CFU plated. All mutants exhibited quinolone-resistant replicative DNA biosynthesis, and 4 of 11 mutants also had decreased amounts of OmpF or OmpC porin. None of the mutants had changes solely in porin proteins.

A sensitive and convenient method for quinolone determination has been developed, based on the natural fluorescence of the quinolone nucleus. Fleroxacin (Ro 23-6240; AM 833), used as a prototype quinolone in these studies, had an excitation maximum at 282 nm and an admission maximum at 442 nm (pH 3.0). Fluorescence intensity was pH dependent, being...

The frequency of fungal infections is increasing as a result of the successful use of anti-bacterials and the proliferation of immunocompromised patients. With the exception of 5-fluorocytosine, all clinically useful antifungals act upon the membrane lipids, inhibiting either their biosynthesis (azoles, allylamines, morpholines) or their function (...

The uptake of quinolone antibiotics by Escherichia coli was investigated by using fleroxacin (RO 23-6240, AM 833) as a prototype compound. The uptake of fleroxacin was reduced and its MIC was increased in the presence of magnesium. Quinolones induced lipopolysaccharide release, increased cell-surface hydrophobicity and outer membrane permeability t...

The penetration of the Escherichia coli outer membrane by two sterically restricted analogs of penicillin G was determined. The analog corresponding to the "open" conformation of penicillin G penetrated faster than the "closed"-form analog did, and both analogs penetrated faster than penicillin G did. The results suggest that the conformation of th...

A series of (2,3)-methylenepenams were examined with respect to binding to essential penicillin-binding proteins (PBPs) in Escherichia coli and Staphylococcus aureus. The compounds were also examined with respect to their interaction with Streptomyces strain R61 DD-carboxypeptidase. The alpha isomer of (2,3)-methylene penicillin G bound to PBP 3 of...

The mode of action of Ro 13-5478 and Ro 14-9578, monocyclic and tricyclic quinolone analogs, respectively, was examined for Escherichia coli and Staphylococcus aureus. The compounds showed antibacterial activity and effects on cell morphology, replicative DNA biosynthesis, and gyrase-catalyzed DNA supercoiling that were comparable to those shown by...

Eight antifungal agents were examined for effects on lipid biosynthesis and membrane integrity in Candida albicans. Lipids were labeled in vivo or in vitro with [14C]acetate and analyzed by thin-layer and gas chromatography. Membrane integrity was measured by a recently developed [14C]aminoisobutyric acid radiolabel release assay. The imidazole ant...

There are four penicillin-binding proteins (PBPs) in Staphylococcus aureus, of which PBPs 2 and 3 are essential. Cefotaxime binds selectively to PBP 2, and cephalexin binds to PBP 3, each at its respective MIC. The morphology of S. aureus strains grown in the presence of the two antibiotics was examined by phase-contrast and scanning electron micro...

The treatment of Candida albicans (yeast form) with digitonin or dimethyl sulfoxide permeabilized cells and caused the activation of chitin synthase in situ. Endogenous activation was completely prevented by the sulfhydryl reagents N-ethylmaleimide, p-chloromercuribenzoate, and 5,5'-dithiobis(2-nitrobenzoic acid); partially prevented by the proteas...

A radiometric assay for measuring the activity of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase is described. The assay is based on the separation of the mevalonate product from HMG-CoA by high-voltage electrophoresis. This method is more sensitive and more specific than the NADPH-based spectrophotometric assay, and less tedious than av...

A fluorometric procedure for measuring the activity of DD-carboxypeptidase is described. The method is based on the reaction of one of the products, D-alanine, with o-phthaldialdehyde to form a highly fluorescent adduct. The method has been applied in examining a series of X-D-alanyl-D-alanine peptides as substrates of the penicillin-sensitive DD-c...

Penicillin and other β-lactam antibiotics inhibit bacterial growth by binding to specific transpeptidases that crosslink peptidoglycan, the rigid bag-like macromolecule, responsible for the mechanical strength of the bacterial envelope. Penicillin acts as a steric analogue of the pentapeptide chain in growing peptidoglycan, forming a stable penicil...