Is There Any Future for Inhibitors of Bacterial Cell Wall Biosynthesis? Karen Bush 21 May 2013
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1 Is There Any Future for Inhibitors of Bacterial Cell Wall Biosynthesis? Karen Bush 21 May May
2 Disclosures ( ) Retiree: Johnson & Johnson, Pfizer (Wyeth), Bristol-Myers Squibb Consultant or Scientific Advisory Board: Allecra, AstraZeneca, Cempra, Cubist, Fedora, GlaxoSmithKline, Medivir, Merck, Rempex, Shionogi, TB Alliance, Wockhardt Research Support: AstraZeneca, Cubist, Forest
3 Points to be Covered Bacterial cell wall Current approved agents Agents in clinical development Future directions 21 May
4 Comparison of the Cell Envelopes of Gram- Positive and Gram-Negative Bacteria Gram-positive b-lactamase Peptidoglycan Gram-negative Lipopolysaccharide Phospholipid b-lactamase Porin uter membrane Cell wall Cell wall Penicillin-binding proteins Cytoplasmic membrane Periplasmic space Peptidoglycan Penicillin-binding proteins Cytoplasmic membrane 21 May
5 Approved Classes of Antimicrobial Agents that Target Cell Wall Biosynthesis Glycopeptides Vancomycin, teicoplanin, telavancin Lipopeptides Daptomycin Phosphonic acids Fosfomycin (phosphonomycin) b-lactams Penicillins, cephalosporins, carbapenems, monobactams b-lactamase inhibitors Clavulanic acid, penicillanic acid sulfones 21 May
6 Advantages All Most important Gram-positive bacteria are in the spectrum Vancomycin Familiar and widely used Highly effective against many Grampositive bacteria Inexpensive Teicoplanin Active against VanB enterococci Telavancin Active against VanB and some VanA enterococci nce-a-day dosing Glycopeptides Vancomycin, teicoplanin, telavancin Disadvantages All Infusion site reactions Vancomycin Questions about dosing and monitoring drug levels Nephrotoxicity 10-20% with normal dosing 30-40% with high doses RESISTANCE in enterococci and staphylococci Telavancin Genotoxicity Nephrotoxicity, QTc prolongation Summarized in: Pucci & Bush. Clin. Micro. Rev Elyasi. Eur. J. Clin. Pharmacol. 68:1243 (2012) 21 May
7 Lipopeptides -- Daptomycin Daptomycin mechanism of action Cell wall? Primary effect on cell membranes Redirects the localization of proteins involved in cell division and cell wall synthesis Dramatic cell wall and membrane defects Ultimately lead to cell death Pogliano, Pogliano & Silverman; J. Bacteriol. 194:4494 (2012) 21 May
8 Advantages Active against most Grampositive bacteria MRSA VRE (in vitro) Approved for right-sided infective endocarditis caused by S. aureus nce-a day dosing Lipopeptides Daptomycin Disadvantages Myopathy, neuropathy, elevated CPK Inactivated by lung surfactant Cannot be used to treat pneumonia Low, but increasing, resistance rates Silverman et al. J. Infect. Dis. 191:2149 (2005); Bayer et al. Annals NYAS, 1277:139 (2013 ) 21 May
9 Fosfomycin Advantages Inhibits MurA, a unique early step in cell wall synthesis Analog of phosphoenol pyruvate, a MurA substrate Broad spectrum activity against Gram-positive and Gram-negatives ral treatment for UTI Disadvantages Rapid selection for resistance Frequently used in combination therapy with other agents Shortage of safety and efficacy data in controlled clinical trials Bergen et al. Curr. pin. Infect. Dis. 25:626 (2012) 21 May
10 b-lactams Advantages Inhibit last step in cell wall synthesis No mammalian homologs Broad spectrum activity against Gram-positive and Gramnegatives Medicinal chemistry wellestablished for drug optimization Safe, efficacious Can be inexpensive Disadvantages Immunological responses ccasional toxicities Nephrotoxic cephalosporins CNS effects from carbapenems RESISTANCE >1300 b-lactamases RESISTANCE altered PBPs RESISTANCE porin defects RESISTANCE efflux RESISTANCE mobile elements with multiple resistance factors 21 May
11 b-lactamase Inhibitors Advantages Restore activity of simple penicillins Avoid unnecessary use of carbapenems and expandedspectrum cephalosporins Inactivators of key class A b- lactamases, not just inhibitors Safe, efficacious ral and IV Disadvantages Lack of broad spectrum activity against all serine b-lactamases No inhibitory activity against metallo-b-lactamases RESISTANCE overproduction of susceptible b-lactamase RESISTANCE b-lactamase variants with reduced affinity RESISTANCE multiple enzymes per strain Summarized in: Pucci & Bush. Clin. Micro. Rev May
12 Investigational Agents in the Pipeline with Cell Wall Activity Phase 1 Phase 2 Phase 3 BAL30072 MK imipenem Dalbavancin Avibactam + aztreonam Avibactam + ceftaroline ritavancin RPX biapenem CXA-201 (ceftolozane + tazobactam) Avibactam + ceftazidime Summarized in: Pucci & Bush. Clin. Micro. Rev May
13 lder Glycopeptides in Late Clinical Development H H N Cl H H H2N H Cl Cl H H HN N H H H N N H H2N H N N H NH Dalbavancin Vicuron to Pfizer Potent anti-staph and VSE activity Abandoned by Pfizer after approvable letter by the FDA requesting additional trials Durata finished trials & is ready to file an NDA this year nce weekly dosing (t 1/2 = 258 h or 11 d) From Pucci & Bush. Clin. Micro. Rev H ritavancin Lilly to InterMune to Targanta to The Medicines Company Anti-staph and VRE (VanA) Approvable letter by FDA requesting additional trials Phase 3 trials for ABSSSI completed Single dose may be effective (t 1/2 = 393 h or 16 d) 21 May H H
14 CXA-201 (Cubist) Ceftolozane + Tazobactam Ceftolozane (FR264205) the novel component of the combination Potent anti-pseudomonal activity MIC 90 = 1 mg/ml against P. aeruginosa resistant to ceftazidime, imipenem and/or ciprofloxacin Vulnerable to hydrolysis by AmpC, serine carbapenemases (KPC) and ESBLs Addition of 4 mg/ml tazobactam resulted in lower ceftolozane MICs 8 mg/ml for 76% of ESBL-producing isolates CTX-M-14 and CTX-M-15 producing strains (most prevalent ESBLs) Juan et al. AAC 54:846 (2010) 21 May
15 Attributes of Non-b-Lactam b-lactamase Inhibitors Structure Spectrum Partner and targeted organisms Avibactam MK-7655 RPX7009 Novel bicyclic non-blactam Ser-carbapenemases (KPCs) AmpC ESBLs Some XAs Ceftazidime (Pseudomonas) Ceftaroline (MRSA) Aztreonam (MBLs) Novel bicyclic non-blactam Ser-carbapenemases (KPCs) AmpC ESBLs Imipenem (Pseudomonas) Boronic acid analog Ser-carbapenemases (KPCs) AmpC ESBLs Biapenem (Pseudomonas) Avibactam (AstraZeneca) MK-7655 (Merck) RPX7009 (Rempex) Summarized in Pucci & Bush. Clin. Micro. Rev May
16 Siderophore Monocyclic b-lactams BAL30072 (Basilea) Monosulfactam with iron chelating dihydropyridone side chain Activity against many Pseudomonas and Acinetobacter MC-1 (Pfizer) Both Similar structural side chain in a monocarbam with activity against nonfermentative bacteria Low resistance selection in contrast to earlier siderophore-substituted b- lactams Stable to hydrolysis by metallo-b-lactamases Page et al. AAC 54:2291 (2010) Flanagan et al. ACS Med CChem Lett 2011, 2: May
17 Why Have Previous Cell Wall Active Agents Failed to be Developed? RESISTANCE develops ahead of clinical development PK/PD considerations Underdosing to lower costs and side effects Competition from agents that still are active against resistant pathogens Risk averse management styles in large Pharma No risk. High benefit. utside compounds are always better than compounds developed by our own scientists 21 May
18 Undeveloped Investigational Cell Wall Inhibitors ral carbapenems and penems (many companies) Tebipenem in Japan Stable against ESBLS, but no anti-pseudomonal activity PK in humans unfavorable compared to once-a-day quinolones Cost-of-goods issues Merck carbapenem patents closed the area to many companies Anti-MRSA b-lactams (many companies) Limited spectrum of activity due to b-lactamase liabilities Nephrotoxicity Mur pathway (many companies) Easy to find enzyme inhibitors, difficult to find agents that work in vivo FtsZ inhibitors (Prolysis/Abgentis) Novel target ring formation -- initiation of cell division In vivo activity, but poor drug-like properties 21 May
19 Future for Cell Wall Active Agents Narrow spectrum b-lactams used in combinations Agents that target Acinetobacter, Pseudomonas Drug-like inhibitors of essential targets like FtsZ Agents with less frequent dosing intervals to minimize length of hospitalization b-lactam or b-lactam-like molecules still viable Monobactam combinations for metallo-b-lactamase-producing organisms Triple b-lactamase inhibitor combinations Broad spectrum agent + Serine b-lactamase inhibitor + Metallo- b- lactamase inhibitor b-lactamase inhibitors with antibacterial activity 21 May
20 ther Combinations of Cell Wall-Active Agents Tedizolid and Daptomycin May 13, 2013 Trius Therapeutics received a notice of allowance from the USPT for a patent application Use of tedizolid phosphate (protein synthesis inhibitor) in combination with daptomycin Claims that sub-therapeutic doses of tedizolid prevent bacterial resistance development when daptomycin is used long term 21 May
21 Conclusions Cell wall active agents have been highly successful No corresponding mammalian targets Safe and efficacious Resistance has been a major factor in their decreasing use The future lies in combinations b-lactamase inhibitors Unusual combinations of cell wall active agents 21 May
22 THANK YU! 21 May
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