The wobbly status of ketolides: where do we stand?

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 catarrhalis as well as atypical pathogens (Mycoplasma pneumoniae, Chlamydia pneumoniae, Legionella pneumophila). Ketolides have extensive tissue distribution, favorable pharmacokinetics (oral, once-a-day) and useful anti-inflammatory/immunomodulatory properties. Hence, they were considered attractive additions to established oral antibacterials (quinolones, ß-lactams, second-generation macrolides) for mild-to-moderate CAP. The first ketolide to be approved, Sanofi-Aventis' telithromycin (RU 66647, HMR 3647, Ketek®), had tainted clinical development, controversial FDA approval and subsequent restrictions due to rare, irreversible hepatotoxicity that included deaths. Three additional ketolides progressed to non-inferiority clinical trials vis-à-vis clarithromycin for CAP. Abbott's cethromycin (ABT-773), acquired by Polymedix and subsequently by Advanced Life Sciences, completed Phase III trials, but its New Drug Application was denied by the FDA in 2009. Enanta's modithromycin (EDP-420), originally codeveloped with Shionogi (S-013420) and subsequently by Shionogi alone, is currently in Phase II in Japan. Optimer's solithromycin (OP-1068), acquired by Cempra (CEM-101), is currently in Phase III. Until this hepatotoxicity issue is resolved, ketolides are unlikely to replace established antibacterials for CAP, or lipoglycopeptides and oxazolidinones for gram-positive infections.

Prospects for new antibacterials: can we do better?

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 includes environmental, opportunistic, but intrinsically multiresistant species: Pseudomonas aeruginosa and Acinetobacter baumannii. Financial considerations have curtailed R&D activity in the antibacterial field in all, but a couple of large pharmaceutical companies and small biotech companies have largely been unable to fill the drug discovery gap. Antibacterials currently under development have targeted, almost exclusively, Gram-positive bacteria; hence, greater effort must be directed against Gram-negative bacteria, particularly enterobacteria. There also has to be more transparency and care in clinical development. To get ahead of the problem of resistance, we must look for first-in-class antibacterials and new targets. The need to innovate is best addressed through partnerships between drug-makers and public institutions. Such partnerships would provide a long-term view and stability to projects, but also balance the interests of corporate and public stakeholders.

Anticancer therapeutics: a surge of new developments increasingly target tumor and stroma.

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. Instead of striving for a comprehensive overview, we showcase several trends, concepts and research areas that exemplify the complexity of drug resistance and its reversal as we currently understand it. Many of the studies discussed here deal with the interaction of tumor cells with their stromal microenvironment; structural proteins as well as cellular components, fibroblasts as well as inflammatory cells. Target identification, target validation and dealing with the challenge of resistance are recurring themes. Specific classes of molecules discussed are the taxanes, tyrosine kinase inhibitors, anti-angiogenic, anti-stromal and anti-metastatic agents. In the latter three categories, targets reviewed are delta-like ligand 4 (DLL4), integrins, nodal, galectins, lysyl oxidases and thrombospondins, several of which belong to the p53-tumor suppressor repertoire of secreted proteins. Finally, developments in other inhibitor classes such as PI3K/Akt and Rho GTPase inhibitors and thoughts on possible novel combination therapies are briefly summarized. The report also includes relevant publications to July 2007.

Anticancer therapeutics: "Addictive" targets, multi-targeted drugs, new drug combinations.

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 as vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor (PDGFR) and the receptor tyrosine kinase KIT - taking centre stage. Several agents interfering with intracellular targets that are components of key oncogenic signaling pathways, such as RAF kinase, phosphatidylinositol 3-kinase (PI3K)/Akt or Src, are in preclinical and early clinical development. "Addictive" targets, such as the Bcr-Abl fusion protein in chronic myeloid leukemia (CML), are critical for maintaining the malignant phenotype and hence represent an Achilles' heel for selective drugs. Significantly, novel targeted therapeutics currently in clinical development do not generally lead to cures or long-term survival for most intractable cancers; resistance may eventually develop. Anti-metastatic agents and anti-adhesion drugs, which collectively act on tumor cell-stroma interactions (anti-stromal therapy), are also actively pursued. In addition, forms of cell death other than apoptosis - cellular senescence, cancer cell-specific cell-cycle processes and the hypoxic environment - are being explored in order to identify novel targets for more selective therapy. This report also highlights developments aimed at more safe and effective drug combinations. Evaluating drug combinations, and elucidating the rationale for combinations of old (cytotoxic) and new (biological) anticancer agents, are promising research areas and taxane-based combinations are presented as examples. The report is based on presentations at AACR 2005 and related publications of the first half of 2005.

Beta-lactamase inhibitors: evolving compounds for evolving resistance targets.

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.g. TEM, SHV) have extended their spectrum (extended-spectrum beta-lactamases and carbapenemases [Sme, NMC-A, IMI-1]) and have brought about the possibility of beta-lactamase-inhibitor resistance. Furthermore, the mobilisation and spread of originally chromosomal class C enzymes (CMY, MIR), the growing clinical importance of class B enzymes (IMP, VIM), the emergence of inhibitor-resistant, broad spectrum class D (OXA) enzymes and the co-existence of different classes of beta-lactamases in the same pathogen have spurred research toward universal inhibitors. A complicating issue is target accessibility in Gram-negative bacteria, particularly in Enterobacter, Acinetobacter, Pseudomonas, Stenotrophomonas and other organisms, which is necessary in order for the inhibitor to synergise with vulnerable beta-lactam antibiotics. Several new, broad-spectrum inhibitors have emerged: cephem sulfones and oxapenems are upgrades of penam sulfones and oxapenams, respectively, with cephem sulfones possibly extending their inhibition to class B metallo-enzymes; and boronates and phosphonates are designed de novo, based on common structural and mechanistic features of serine beta-lactamases.

New cancer therapeutics: target-specific in, cytotoxics out?

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 trends in anti-cancer research. One of the most exciting areas was the development of molecular target-specific therapeutics that have the potential to maximize therapeutic benefit while minimizing toxicity to normal cells. Signifying the coming of age of tumour-specific targets and agents was the recurring theme, to urgently develop and validate biomarker assays as surrogate endpoints; both for showing that targeted agents act as expected and for providing proof of concept in the scientific rationale of new agents. Given the dominance of protein tyrosine kinase inhibitors in small-molecule drug design, a strong case was made for the implementation of phospho-proteomics or signal transduction signatures and pharmaco-proteomics or chemotherapeutic scans in phase I/II trials--or for the future "Nanolab", eloquently described by Leroy Hood. However, molecular targeted agents-other than imanitib (Gleevec)--have yet to enter broad clinical use and several presentations described efforts for improving classical (cytotoxic) chemotherapeutic agents by targeting them selectively to tumour cells.

Mechanism of action of NB2001 and NB2030, novel antibacterial agents activated by beta-lactamases.

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 exploit beta-lactamases to release triclosan through hydrolysis of the beta-lactam ring. Like cephalothin, NB2001 and NB2030 were hydrolyzed by class A beta-lactamases (Escherichia coli TEM-1 and, to a lesser degree, Staphylococcus aureus PC1) and class C beta-lactamases (Enterobacter cloacae P99 and E. coli AmpC) with comparable catalytic efficiencies (k(cat)/K(m)). They also bound to the penicillin-binding proteins of S. aureus and E. coli, but with reduced affinities relative to that of cephalothin. Accordingly, they produced a cell morphology in E. coli consistent with the toxophore rather than the beta-lactam being responsible for antibacterial activity. In biochemical assays, they inhibited the triclosan target enoyl reductase (FabI), with 50% inhibitory concentrations being markedly reduced relative to that of free triclosan. The transport of NB2001, NB2030, and triclosan was rapid, with significant accumulation of triclosan in both S. aureus and E. coli. Taken together, the results suggest that NB2001 and NB2030 act primarily as triclosan prodrugs in S. aureus and E. coli.

Infectious disease 2001: drug resistance, new drugs.

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, microbial pathogenesis and emerging pathogens, to infection control, vaccines, antibiotic resistance and new antimicrobial agents and treatment strategies. Summarized here are highlights on bacterial and fungal drug resistance and on new agents in preclinical and clinical development.

Antifungals targeted to protein modification: focus on protein N-myristoyltransferase.

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). The first is a fungistatic target vulnerable to resistance development; the second, while a fungicidal target, is not sufficiently different from the host to ensure high selectivity; the third, a fungistatic (Aspergillus) or fungicidal (Candida) target, has limited activity spectrum (gaps: Cryptococcus, emerging fungi) and potential host toxicity that might preclude dose escalation. Drugs aimed at totally new targets are thus needed to increase our chemotherapeutic options and to forestall, alone or in combination chemotherapy, the emergence of drug resistance. Protein N-myristoylation, the cotranslational transfer of the 14-carbon saturated fatty acid myristate from CoA to the amino-terminal glycine of several fungal proteins such as the ADP-ribosylation factor (ARF), presents such an attractive new target. The reaction, catalysed by myristoyl-CoA:protein N-myristoyltransferase (NMT), is essential for viability, is biochemically tractable and has proven potential for selectivity. In the past five years, a number of selective inhibitors of the fungal enzyme, some with potent, broad spectrum antifungal activity, have been reported: myristate analogues, myristoylpeptide derivatives, histidine analogues (peptidomimetics), aminobenzothiazoles, quinolines and benzofurans. A major development has been the publication of the crystal structure of Candida albicans and Saccharomyces cerevisiae NMTs, which has allowed virtual docking of inhibitors on the enzyme and refinement of structure-activity relationships of lead compounds.

Infectious disease 2000: drug resistance and new drugs.

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 antimicrobial agents. Summarized here are highlights on microbial resistance and agents in clinical and preclinical development. Copyright 2000 Harcourt Publishers Ltd.