what’s new in the antimicrobial r&d pipeline · basarab, g. top. med. chem..2017. 16 protein...
TRANSCRIPT
What’s New in the Antimicrobial R&D Pipeline
Greg Basarab
7th FIDSSA Conference
November 11, 2017
A Gap in Time for Novel Antibacterial Classes
Sulfa Drugs 1935
-Lactams 1942
Tetracyclines, 1949
Chloramphenicol
Macrolides 1952
Glycopeptides 1958
Streptogramins, 1962-3
Lincomycins,
Quinolones
Aminoglycosides 1947
1920 1940 1960 1980 2000 2020
>35 year gap Oxazolidinones 2000
Cyclic Lipopeptides 2003
Diarylquinolines 2012
For Gram-(-)’s: 53 year
gap & counting
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Mechanistic Classes of Antibacterial Agents
Protein synthesis inhibitors
Inhibitors of peptidoglycan
biosynthesis
DNA topoisomerase
inhibitorsFolate antagonists
Beta-lactams
– penicillins
– cephalosporins
– penems
– carbapenems
– monobactams
Glycopeptides
– e.g. vancomycin
Aminoglycosides
– e.g. gentamicin
Oxazolidinones
– e.g. linezolid
Chloramphenicol
– e.g. thiamphenicol
Lincosamides
– e.g. clindamycin
Aminocyclitols
– e.g. spectinomycin
Tetracyclines
– e.g. doxycycline
Macrolides
– e.g. erythromycin
Streptogramins
– e.g. quinupristin
Pleuromutilins
– e.g. retapamulin
Quinolones
– e.g. ciprofloxacin
ATPase inhibitors
– e.g. novobiocin
Sulfonamides
Trimethoprim
Iclaprim
RNA replication
inhibitorsRifamycins
– e.g. rifampin
Polymixins
– e.g. colistin
Membrane disruption
Membrane depolarization
Cyclic lipopeptides
– e.g. daptomycin
Free radical generator
Metronidazole
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1
2
1
5
1
5
4
Clinical -lactamase Inhibitors
NDAAdjunct
toDrug
-Lactamase Class
A B C D
Clavulanic acid
1984
1990
amoxicillin
ticarcillin
co-amoxiclav
co-ticarclav
Sulbactam
1991
1994
ampicillin
ampicillin
Unasyn
sultamicillin(prodrug)
Tazobactam
1993
2014
piperacillin
ceftolozane
Tazosyn
Zerbaxa
Avibactam
2015 ceftazidime Zaficefta (±)
• No coverage against class B, zinc and bis-zinc metallo--lactamases• No coverage against key class D -lactamases
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-Lactamase Primer
Class TypePeni-cillins
Cephalo-sporins(ESBLs)
Carba-penems
Mono-bactams
Represen-tatives
A(2a-2f)
serine 2bc,2ber,
2e,2f2f 2be,2f
TEM-1,30,50,121
SHV-1,10CTX-M014,15
B(B1a-b, B2, B3)
Zn2+
2 x Zn2+ 3a noIMP-VIM
NDM-1
C(1, 1e)
serine no 1e no no
AmpCACT-1CGY
CMY-37
D(2d,2de,
2df)serine no 2d,2de
Oxa1,10,11,15,23,48
Bush, K. J. Inf. Chemother. 19(4), 2013, 549
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-lactamase inhibitors
-lactamase with PBPIs
PhaseIndications/
Target Pathogens
Mode of
Administration
Vabormere: vaborbactam (boronate) +
meropenemNDA cUTI, HABP/VABP IV
Relebactam (DABCO) + imipenem +
cilastatin3 HABP/VABP IV
Zidebactam (DABCO) + cefepime 1CRE
(ESBLs & KPCs)IV
Nacubactam (DABCO) + meropenem? 1 CRE IV
AAI-101 (-lactam) + cefepime or
piperacillin1
CRE
(ESBLs & KPCs)IV
VNRX-5133 (boronate) +
unknown antibiotic1 MBL producers IV
ETX2514 + sulbactam
(DABCO)1 Aba IV
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Boronate BLI’s
▪ Vaborbactam + meropenemoptimized against KPC mode-of-resistance
▪ Pathogen specific development path for CRE
▪ NDA approval – Aug. 2017 for cUTI(The Medicines Co.) Enterobacteriaceae infections
VNRX-5133 + unknown (IV) – VenatoRX▪ Pre-clinical metallo--lactamase
inhibitor▪ Structure not disclosed▪ Tetrahedral boronate mimics
hydrolytic high-energy intermediate▪ Phase 1
Hecker et al. J. Med. Chem. 58(9), 2015, 3862Jones, RM et al. AAC, 60(9), 2016, 5454
Brem et al. AAC 61(4), 2017, e02260
208 KPC strains K. pneumoniae MP
VB(8 g/ml)
+MP
MIC50
g/ml
16 <0.06
MIC90 >64 1
K. pneumoniaeSHV-11; VIM-2
Mero-penem
Boronate + meropenem
MIC (g/ml)
>8 0.5
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Extended spectrum DABCO BLIETX2514 – Class A
Class C Class D
▪ Covalent reactivity increased due to strain
▪ Combination w/ sulbactamagainst A. baumannii
▪ Phase 1 (Entasis Therapeutics from AstraZeneca)
Durant-Reville et al. Nat. Microbiol. 2(9), 2017, 17104
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-Lactam antibacterials
Inhibitors of penicillin binding proteins (PBPs)
Phase IndicationsMode of
Administration
Cefiderocol –
(siderophore cephalosporin)3 HAP IV
Sulopenem (penem) 3 UTI, cIAI PO & IV
GSK-3342830
(siderophore cephalosporin)1 HPA/VAP IV
LYS-228 (monobactam) 1 CRE IV
AIC-449 (monobactam) + BLI? 1 TBD IV
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Novel cephalosporin and novel penem
Sulopenem (IV) – Pfizer (1988)Sulopenem etzadroxil –(PO pro-drug) Iterum Therapeutics▪ Carbapenem-like spectrum (but
lacking Pseudomonas)▪ Carbapenem-like resistance profile▪ Enterobacteriaceae spectrum for
uUTI, cUTI & cIAI▪ Phase 3 – to begin end of 2017
Cefiderocol (IV) - Shionogi▪ Siderophore Fe2+ chelator for
‘Trojan-horse’ uptake into bacterial periplasm
▪ Pseudomonas activity (elevated MICs)
▪ Enterobacteriaceae spectrum –elevated MICs for KPCs
▪ Phase 3 for HAP/VAP
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2nd Generation Monobactams
LYS-228 (IV) - Novartis▪ Phase 1▪ Enterobacteriaceae spectrum –▪ MIC90’s = 0.25 g/ml (wild-type)
0.5 g/ml (ESBLs/AmpC)4.0 g/ml (carbapenemases)
AIC-449 (IV) - AiCuris▪ Phase 1, structure not disclosed▪ Partner BLI combination
➢ Stable to metallo--lactamases (Class B)➢ Greater stability vs aztreonam to serine -lactamases (Class A, C & D)
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Type-II Topoisomerase Inhibitors
Fluoroquinolines, Quinolines, Spiropyrimidinetriones
Phase IndicationsMode of
Administration
Delafloxacin (FQ) NDA cSSTI; CAP PO &IV
Lascufloxacin (FQ) 3 RTI; CAP PO &IV
Finafloxacin (FQ) 2 aEI PO &IV
Gepotidacin (quinoline) 2 cSSTI; STD PO &IV
Zoliflodacin (SPT) 2 STD PO
Alalevonadifloxacin (FQ) 1 cSSTI PO
TNP-2092 (FQ/Rif hybrid) 1 PJI PO
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FQ-type + Rifampicin
TNP-2092 (IV) – TenNor Therapeutics▪ Gram-(+) agent for prosthetic
joint infections
Ma, Z. J.. Med. Chem.. 59, 2016, 6645..
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Novel Bacterial Topoisomerase Inhibitors (NBTIs)
Zoliflodacin (PO)- Entasis (from AstraZeneca)▪ Activity against Gram-(+) and fastidious
Gram-(-)▪ Phase 3 in 2018 targeting uncomplicated
gonorrhea▪ No cross-resistance to FQs and other
antibacterial agents
Gepotidacin (IV & PO) – GSK▪ Activity against Gram-(+) and
fastidious Gram-(-)▪ Phase 2 for gonorrhea and cSSSI▪ No cross-resistance to FQs and
other antibacterial agents
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Topoisomerase Target
GepotidacinBinds to Gyrase/DNA complex
MoxifloxacinBinds to Gyrase/cleaved DNA complex
Dependent on Mg2+
Zoliflodacin• Binds to Gyrase/cleaved DNA complex• Independent of Mg2+
DNA Gyrase – creates negative supercoils in dsDNATopoisomerase IV – decantenates intertwined dsDNA
Basarab, G. Top. Med. Chem..2017.
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Protein biosynthesis inhibitors
Ribosome inhibitors
Phase IndicationsMode of
Administration
Plazomicin (aminoglycoside) 3 cUTI, HAP/VAP IV
Eravacycline (tetracycline) 3 cIAI, cUTI PO & IV
Omadacycline (tetracycline) 3 CAP, cSSTI PO & IV
Solithromycin (macrolide) 3 CAP PO & IV
Nafithromycin (macrolide) 2 CAP PO
TP-271 (tetracycline) 1 CAP PO & IV
TP-6076 (tetracycline) 1 CRE PO & IV
KBP-7072 (tetracycline) 1 CAP PO & IV
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Translation Inhibitors
Plazomicin (IV)- Achogen▪ Unaffected by aminoglycoside-modifying
enzymes▪ Susceptible to 16S rRNA methylase▪ Phase 3 against cUTI; HAP/VAP
Eravacycline (PO & IV)- Tetraphase▪ Fully synthetic tetracycline▪ Unaffected by Tet(M)-rpp
Tet(X)-metabolizing ▪ Susceptible to Tet(A)-efflux▪ Phase 3 for IAI, UTI
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Membrane Disrupters
Colistins & Defensins
Phase IndicationsMode of
Administration
Murepavidin (POL-7080)Cyclic peptide binds to lpt1
2VAP, RTI
(Pseudomonas only)
IV
Brilacidin 2 SSTI IV
SPR-741 (cyclic peptide potentiator) + unknown
1 TBD IV
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Gram-positive arena
Others
Phase IndicationsMode of
Administration
Cadezolid (Oxa-FQ hybrid) 3 C. difficile PO
Lefamulin (pleuromutilin) 3 Gram-(+) PO & IV
MRX-I/MRX-4 (oxazolidinone) 2/3 Gram-(+) PO & IV
Afabicin (FabI inhibitor) 2 Gram-(+) PO & IV
Ridinilazole (bis-benzimidazole) 2 C. difficile PO
MGB-BP-3 (minor groove binder) 1 C. difficile PO
MCB3837 (Oxa-FQ hybrid) 1 C. difficile PO
Sutezolid (Oxa) 1 Mtb PO
TBA-7371 (DprE1 inhibitor) 1 Mtb PO
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Parting thoughtsWHO: pipeline is insufficient to meet needs over the next decade
• Novel mode-of-action drugs in the pipeline: 4 – all Ph 1; none for Gram-(-)’s
• Novel mode-of-inhibition drugs in the pipeline: 4 - none for serious Gram-(-)’s
• Novel chemical scaffolds in the pipeline: 7
J. Rex, ASM_ESCMID, 2017, Boston
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More parting thoughts
Timing is right to push forward
• The medical community has prioritized new and expanded infectious disease
control measures
• New medicines
• Rapid diagnostics
• Access to care
• Improved medical practices
• Issues of antibiotic resistance are high on the political agenda (not just the
medical community agenda)
• High profile public/private/philanthropic partnerships & initiatives have recently
been created or been directed at AMR/DRI
• CARB-X
• GARD-P
• Ross Foundation
• Longitudeprize.org
• Wellcome-Trust
• IMI
• GAMRIF
• NIAID
Title
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About H3D
• Founded in 2010 as a University of Cape Town (UCT) accredited research centre
• Current staff of 55 scientists and support including Post Doctoral Fellows (August 2017)
• Drug discovery platform located at three sites across two campuses
Dept of Chemistry
Dept of Pharmacology
IDM
Department of Chemistry
Department of MedicineIDM
H3D is the first and only fully integrated drug discovery unit in Africa and we target neglected infectious diseases that are relevant to African populations
Capabilities
In Vitro ADME
In Vivo PK
Assay DevelopmentDMPK
Medicinal Chemistry
CADD
Ch
em
istry
MicrobiologyTB & Gram-(-)
Biology
Malaria Biology
Cytotoxicity cross-screening