Post on 02-Aug-2020
Is There Any Future for Inhibitors of Bacterial Cell Wall Biosynthesis?
Karen Bush
21 May 2013
21 May 2013 1
Disclosures (2012-2013)
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
Points to be Covered
• Bacterial cell wall
• Current approved agents
• Agents in clinical development
• Future directions
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Comparison of the Cell Envelopes of Gram-Positive and Gram-Negative Bacteria
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b-lactamase
Peptidoglycan
Peptidoglycan
Gram-positive Gram-negative
Lipopolysaccharide Phospholipid
b-lactamase Porin Outer membrane
Cell wall Cell wall
Cytoplasmic membrane
Cytoplasmic membrane
Periplasmic space Penicillin-binding proteins
Penicillin-binding proteins
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
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Glycopeptides
Advantages – All
• Most important Gram-positive bacteria are in the spectrum
– Vancomycin • Familiar and widely used • Highly effective against many Gram-
positive bacteria • Inexpensive
– Teicoplanin • Active against VanB enterococci
– Telavancin • Active against VanB and some VanA
enterococci • Once-a-day dosing
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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
Elyasi . Eur. J. Clin. Pharmacol. 68:1243 (2012) Summarized in: Pucci & Bush. Clin. Micro. Rev. 2013
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
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Pogliano, Pogliano & Silverman; J. Bacteriol. 194:4494 (2012)
Lipopeptides
Advantages
– Active against most Gram-positive bacteria • MRSA
• VRE (in vitro)
– Approved for right-sided infective endocarditis caused by S. aureus
– Once-a day dosing
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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 )
Fosfomycin
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Disadvantages
– Rapid selection for resistance
– Frequently used in combination therapy with other agents
– Shortage of safety and efficacy data in controlled clinical trials
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
– Oral treatment for UTI
Bergen et al. Curr. Opin. Infect. Dis. 25:626 (2012)
b-Lactams
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Advantages
– Inhibit last step in cell wall synthesis
– No mammalian homologs
– Broad spectrum activity against Gram-positive and Gram-negatives
– Medicinal chemistry well-established for drug optimization
– Safe, efficacious
– Can be inexpensive
Disadvantages
– Immunological responses
– Occasional 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
b-Lactamase Inhibitors
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Advantages
– Restore activity of simple penicillins
– Avoid unnecessary use of carbapenems and expanded-spectrum cephalosporins
– Inactivators of key class A b-lactamases, not just inhibitors
– Safe, efficacious
– Oral 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. 2013
Investigational Agents in the Pipeline with Cell Wall Activity
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Phase 1 Phase 2 Phase 3
BAL30072 MK7655 + imipenem Dalbavancin
Avibactam + aztreonam
Avibactam + ceftaroline
Oritavancin
RPX7009 + biapenem CXA-201 (ceftolozane + tazobactam)
Avibactam + ceftazidime
Summarized in: Pucci & Bush. Clin. Micro. Rev. 2013
Older Glycopeptides in Late Clinical Development
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
– Once weekly dosing (t1/2 = 258 h or 11 d)
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Oritavancin
– 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 (t1/2 = 393 h or 16 d)
O
O O
O
O
NH
Cl Cl
OH
HN
O
O
OH
OH
OHN
O OH
HN
NH
O
NH
OH
OH2N
O
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O
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From Pucci & Bush. Clin. Micro. Rev. 2013
CXA-201 (Cubist) Ceftolozane + Tazobactam
• Ceftolozane (FR264205) – the novel component of the combination
– Potent anti-pseudomonal activity
– MIC90 = 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)
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Juan et al. AAC 54:846 (2010)
Attributes of Non-b-Lactam b-Lactamase Inhibitors
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Avibactam MK-7655 RPX7009
Structure Novel bicyclic non-b-lactam
Novel bicyclic non-b-lactam
Boronic acid analog
Spectrum Ser-carbapenemases (KPCs)
AmpC ESBLs Some OXAs
Ser-carbapenemases (KPCs)
AmpC ESBLs
Ser-carbapenemases (KPCs)
AmpC ESBLs
Partner and targeted organisms
Ceftazidime (Pseudomonas)
Ceftaroline (MRSA) Aztreonam (MBLs)
Imipenem (Pseudomonas)
Biapenem (Pseudomonas)
Avibactam (AstraZeneca) MK-7655 (Merck) RPX7009 (Rempex)
Summarized in Pucci & Bush. Clin. Micro. Rev. 2013
Siderophore Monocyclic b-Lactams
• BAL30072 (Basilea)
– Monosulfactam with iron chelating dihydropyridone side chain
– Activity against many Pseudomonas and Acinetobacter
• MC-1 (Pfizer)
– Similar structural side chain in a monocarbam with activity against non-fermentative bacteria
• Both
– Low resistance selection in contrast to earlier siderophore-substituted b-lactams
– Stable to hydrolysis by metallo-b-lactamases
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Page et al. AAC 54:2291 (2010) Flanagan et al. ACS Med CChem Lett 2011, 2:385
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.”
– Outside compounds are always better than compounds developed by our own scientists
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Undeveloped Investigational Cell Wall Inhibitors
• Oral 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
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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
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Other Combinations of Cell Wall-Active Agents
• Tedizolid and Daptomycin
– May 13, 2013
– Trius Therapeutics received a notice of allowance from the USPTO 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
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http://triusrx.com/
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
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THANK YOU !
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