Simposio 4: “Strategies for the design and development of new drugs”
DESIGN STRATEGIES FOR NEW CLASSES OF ANTIBACTERIAL DRUGS, A HOPE IN A POST-ANTIBIOTIC ERA.
Dr. David Vásquez Velásquez Departamento de Química Farmacológica y toxicológica Facultad de Ciencias Químicas y Farmacéuticas Universidad de Chile
Miércoles 06 Noviembre del 2019 16:48 1 DESIGN STRATEGIES FOR NEW CLASSES OF ANTIBACTERIAL DRUGS, A HOPE IN A POST-ANTIBIOTIC ERA.
A HOPE IN A POST-ANTIBIOTIC ERA
16:48 2 Aminoglycosides
1930 1940 1950 Tetracyclines Lincosamides Macrolides Sulfonamides Beta-lactams Cycloserine Chloramphenicol Glycopeptides Quinolones Polypeptides Rifampicin 1980 1970 1960 Nitroimidazoles
Trimethoprim New Drugs Families Under Development Mupirocin
1990 2000 2010 TODAY
Oxazolidinediones Lipopeptides
Streptogramins A HOPE IN A POST-ANTIBIOTIC ERA
Nº of Antibacterial drugs approved by FDA (1983-2016)
WHY HAS THE DEVELOPMENT OF ANTIBACTERIALS 16 AGENTS DRASTICALLY DECREASED? 14
10
7 5 5 1. Return on Investment (ROI) 1983-1987 2 1988-1992 1993-1997 1998-2002 2003-2007 2008-2012 2. Drug-resistant 2013-2016
3. Serious adverse reaction Chronology of the introduction of antibacterial agent and resistance report. Introduction of Drug Resistance Report Year Drug Year Species 1940 penicillin 1943 penicillin-resistant S. aureus 1959 polymyxin E 2016 polymyxin E-resistant E. coli 1960 methicillin 1962 methicillin-resistant S. aureus 1967 gentamicin 1979 gentamicin-resistant Enterococcus spp.
1972 vancomycin 1988 vancomycin-resistant Enterococcus spp.
1996 levofloxacin 1996 levofloxacin-resistant S. pneumoniae 2000 linezolid 2001 linezolid- resistant S. aureus 2003 daptomycin 2005 daptomycin not susceptible to S. aureus
Chronology of the antibacterial drugs approvals in the last decade. Commercial Year Active principle FDA Approved indication Name Complicated intra-abdominal infections in combination with 2019 Xenleta® lefamulin Community acquired bacterial pneumonia 2014 Zerbaxa® ceftolozane - tazobactam metronidazole and complicated urinary tract infections, including pyelonephritis. 2018 Zemdri® plazomicin Complicated urinary tract infections Orbactiv® oritavancin Skin infections. Xerava® eravacycline Complicated intra-abdominal infections Sivextro® tedizolid phosphate Skin infections. Community-acquired bacterial pneumonia and acute bacterial skin and Nuzyra® omadacycline Dalvance® dalbavancin skinSkin structureinfections. infections Aemcolo® rifamycin Traveler's diarrhea 2013 No antibacterial drugs approvals reported
20172012 Vabomere® meropenem - vaborbactamNo antibac terialComplicated drugs approvals urinary tract reported infections
2011 BaxdelaDificid®® delafloxacinfidaxomicin AcuteClostridium bacterial difficile skin-associated infections diarrhea. Complicated skin and soft tissue infections and Community-acquired 2010 SoloZinforo®sec® secnidazoleceftaroline fosamil Bacterial vaginosis pneumonia 20162009 Vibativ® telavancin No antibacterialComplicated drugs approvals skin and reportedskin structure infections. Complicated intra-abdominal infections in combination with 20152008 Avycaz® ceftazidime - avibactamNo antibacterialmetronidazole, drugs approvals and complicated reported urinary tract infections, including pyelonephritis.Complicated intra -abdominal infections and complicated urinary tract 2007 Doribax® doripenem Complicatedinfections, including intra-abdominal pyelonephritis infections. in combination with 2014 Zerbaxa® ceftolozane - tazobactam metronidazole and complicated urinary tract infections, including pyelonephritis. Orbactiv® oritavancin Skin infections.
Sivextro® tedizolid phosphate Skin infections.
Dalvance® dalbavancin Skin infections.
2013 No antibacterial drugs approvals reported
2012 No antibacterial drugs approvals reported
2011 Dificid® fidaxomicin Clostridium difficile-associated diarrhea. Complicated skin and soft tissue infections and Community-acquired 2010 Zinforo® ceftaroline fosamil pneumonia
Chronology of the antibacterial drugs approvals in the last decade. Commercial Year Active principle FDA Approved indication Name 2019 Xenleta® lefamulin Community acquired bacterial pneumonia
2018 Zemdri® plazomicin Complicated urinary tract infections
Xerava® eravacycline Complicated intra-abdominal infections Community-acquired bacterial pneumonia and acute bacterial skin and Nuzyra® omadacycline skin structure infections Aemcolo® rifamycin Traveler's diarrhea
2017 Vabomere® meropenem - vaborbactam Complicated urinary tract infections
Baxdela® delafloxacin Acute bacterial skin infections
Solosec® secnidazole Bacterial vaginosis
2016 No antibacterial drugs approvals reported Complicated intra-abdominal infections in combination with 2015 Avycaz® ceftazidime - avibactam metronidazole, and complicated urinary tract infections, including pyelonephritis. Complicated intra-abdominal infections in combination with 2014 Zerbaxa® ceftolozane - tazobactam metronidazole and complicated urinary tract infections, including pyelonephritis. Orbactiv® oritavancin Skin infections.
Sivextro® tedizolid phosphate Skin infections.
Dalvance® dalbavancin Skin infections.
2013 No antibacterial drugs approvals reported
2012 No antibacterial drugs approvals reported
2011 Dificid® fidaxomicin Clostridium difficile-associated diarrhea. Complicated skin and soft tissue infections and Community-acquired 2010 Zinforo® ceftaroline fosamil pneumonia
WHO priority pathogens list for drug development of new antibacterial agents. Priority Pathogens carbapenem-resistant Acinetobacter baumannii, Critical carbapenem-resistant Pseudomonas aeruginosa, carbapenem-resistant and ESBL-producing Enterobacteriaceae vancomycin-resistant Enterococcus faecium methicillin-resistant, vancomycin-intermediate and resistant Staphylococcus aureus clarithromycin-resistant Helicobacter pylori High fluoroquinolone-resistant Campylobacter spp fluoroquinolone-resistant Salmonellae fluoroquinolone-resistant and cephalosporin-resistant Neisseria gonorrhoeae penicillin-non-susceptible Streptococcus pneumoniae Medium ampicillin-resistant Haemophilus influenzae fluoroquinolone-resistant Shigella spp. DESIGN STRATEGIES FOR NEW CLASSES OF ANTIBACTERIAL DRUGS, A HOPE IN A POST-ANTIBIOTIC ERA.
NEW CLASSES OF ANTIBACTERIAL DRUGS
NEW CLASSES ANTIBACTERIAL DRUGS
16:48 9 ANTIBACTERIAL DRUGS NO Concept Cell integrity No threat DEFEND
Cause No antibacterial Drug
Effect Normal Parameters
16:48 10 ANTIBACTERIAL DRUGS NO Concept Cell integrity No threat DEFEND
No antibacterial Drug
Design
Analysis
Test
16:48 11 ANTIBACTERIAL DRUGS DEFEND Bacteria integrity Concept Threat
Cause Antibacterial Drug
Effect Normal Parameters
16:48 12 ANTIBACTERIAL DRUGS DEFEND Bacteria integrity Concept Threat
Antibacterial Drug
Design
Analysis
Bacteria Bacteria Test susceptible Resistant
Mechanism 16:48 13 ANTIBACTERIAL DRUGS DEFEND Bacteria integrity Concept Threat
Antibacterial Drug
Specific
Mechanism NEW CLASSES
Nonspecific
Bacteria Bacteria susceptible Resistant
Mechanism 16:48 14 NEW CLASSES OF ANTIBACTERIAL DRUGS Concept
Attack an evolutionary conserved mechanism, fundamental to the survival of the bacteria.
It attacks a new mechanism, not present in the known antibacterials.
Synthetic structure, different from those presented in nature.
Pharmacological target specific to bacteria.
Null or low toxicity.
16:48 15 ANTIBACTERIAL AGENTS WITH KNOWN MECHANISM OF ACTION IN CLINICAL DEVELOPMENT.
16:48 16 THERAPEUTIC APPLICATION DEVELOPMENT PHASE Class: Thiopenem Name: Sulopenem Bacterial pneumonia II
Imipenem 16:48 17 3PBQ - Crystal structure of PBP3 complexed with imipenem
16:48 18 4H8R - Imipenem complex of GES-5 carbapenemase
16:48 19 THERAPEUTIC APPLICATION DEVELOPMENT PHASE
Community-acquired pneumonia, chronic obstructive pulmonary III disease and uncomplicated urogenital gonorrhea Carbamate ring
Class: Macrolide Name: Solithromycin Telithromycin
16:48 20
16:48 22 16:48 23 ANTIBACTERIAL AGENTS WITH NEW MECHANISMS OF ACTION, IN CLINICAL DEVELOPMENT.
16:48 24 Triclosan Target: Enoyl ACP-reductase (FabI) Class: FabI inhibitor Name: Debio1452 Activity: FabI is implicated in the last step in the fatty acid biosynthetic pathway. This biosynthetic cycle results in elongation of the fatty acid by two carbons, an acetate unit, during each cycle.
Effect: The FabI inhibition prevents elongation of the acyl chain, disrupting both saturated and unsaturated fatty acid biosynthesis and preventing bacterial growth.
The overexpression of FabI in S. aureus rise to an Name: Debio1450 Class: FabI inhibitor increase in the MIC. Prodrug: afabicin 16:48 25 Class: FabI inhibitor Name: Debio1452
16:48 26 Flamm, R. K.; Rhomberg, P. R.; Kaplan, N.; Jones, R. N.; Farrell, D. J., Activity of Debio1452, a Activity of Debio1452, a FabI Inhibitor with Potent Activity against Staphylococcus aureus and Coagulase- Negative Staphylococcus spp., Including Multidrug-Resistant Strains. Antimicrobial agents and chemotherapy 2015, 59, (5), 2583-2587. Class: FabI inhibitor Name: CG400549
16:48 27 16:48 28 16:48 29 16:48 30 ANTIBACTERIAL AGENTS WITH KNOWN MECHANISM OF ACTION IN CLINICAL DEVELOPMENT.
ANTIBACTERIAL AGENTS WITH NEW MECHANISMS OF ACTION, IN CLINICAL DEVELOPMENT.
16:48 31 Aminoglycosides
1930 1940 1950 Tetracyclines Lincosamides Macrolides Sulfonamides Beta-lactams Cycloserine Chloramphenicol Glycopeptides Quinolones Polypeptides Rifampicin 1980 1970 1960 Nitroimidazoles
Trimethoprim New Drugs Families Under Development Mupirocin Defensin-mimetic FabI inhibitors LptD inhibitors
1990 2000 2010 TODAY
Oxazolidinediones Lipopeptides PDF inhibitors LeuRS-tRNA inhibitors Streptogramins 16:48 33