Why is it so hard to discover develop antibacterial drugs for Gram negative bacteria? Lynn L. Silver, Ph.D. LL Silver Consulting, LLC
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1 Why is it so hard to discover develop antibacterial drugs for Gram negative bacteria? Lynn L. Silver, Ph.D. LL Silver Consulting, LLC
2 2 The Innovation gap in novel classes Obscures the Discovery void Discovery Innovation void gap Quinolones, Streptogramins Mutilins Glycopeptides Lipopeptides Macrolides Oxazolidinones Aminoglycosides Chloramphenicol, Tetracyclines - lactams Sulfa drugs Between 1962 and 2000, no major classes of antibiotics were introduced No registered classes of antibiotics were discovered after 1987 Fischbach and Walsh, 2009
3 3 Failure to find new antibacterials during this period Due largely to reliance on using novel targets to screen/design in vitro inhibitors without paying attention to the obstacles to further development 1. Inhibitors of single enzyme targets are likely to select for rapid resistance [in the lab] 2. Compounds discovered active in vitro may will have a hard time entering bacteria 1. Much more problematic in Gram-negatives 2. Compound libraries not compatible with bacterial entry
4 Periplasm 4 -lactams Glycopeptides Cycloserine Fosfomycin CM Rifampin Gram-positive Cytoplasm Aminoglycosides Tetracyclines Chloramphenicol Macrolides Lincosamides Oxazolidinones Fusidic Acid Mupirocin Gram-negative P. aeruginosa Cytoplasm Novobiocin Fluoroquinolones Sulfas Trimethoprim Metronidazole Daptomycin Polymyxin For Gram-negatives, limiting factors are entry and efflux CM OM
5 5 Gross Structural Differences peptidoglycan cell wall peptidoglycan cell wall cytoplasm Gram Negative Bacteria cytoplasm Ga Gram Positive Bacteria Target Location is Key If the target is in the Gram-negative cytoplasm, then the drug must traverse 2 membranes and avoid efflux If the target is in the periplasm [as are the PBPs, targets of β-lactams], then the drug needs only to traverse the outer membrane and avoid efflux
6 6 Cytoplasmic membrane (CM) barrier Diffusion through a phospholipid bilayer like the cytoplasmic membrane (CM) requires uncharged, lipophilic species ATP ADP+Pi CM Polar, hydrophilic, charged compounds require active transport However, active transport permeases have not been found for most marketed antibacterials
7 7 Gram negative barriers The Outer Membrane (OM) of gram negatives adds an orthogonal barrier to that of the cytoplasmic membrane OM periplasm CM ATP Penetration of the OM through porins prefers small (<600 MW) hydrophilic, charged compounds But highly charged molecules can t penetrate the CM (unless actively transported) Molecules that do penetrate can be effluxed from the cytoplasm or periplasm What kind of molecules can enter the gram negative cytoplasm?
8 clogp 8 Cytoplasm-targeted antibacterials compounds 6.0 Gram negative cytoplasmic entry by diffusion Gram positive only chloramphenicol 4.0 tetracycline ciprofloxacin Cytoplasmic O 2 N O O OH Cl OH N F OH OH Cl NH O 2 N N HO OH OH O OH O O HN metronidazole -2.0 N O N 2 N -4.0 OH nitrofurantoin O 2 N O O N N NH O sulfamethoxazole trimethoprim H 2 N O O S NH N O NH 2 Cytoplasmic energy N dependent transport H 2 N N O O O MW LL Silver Exp. Opin. Drug Disc. 3:
9 9 Are there rules for G- entry by diffusion? Can a set of rules be arrived at With sufficient data from many more chemotypes Measurement of entry not dependent on activity Chemical descriptors clogd at ph 6.5 through 8 MW pka / charge Radius PSA etc clogd to +2 MW < 500 Charge ph to 0
10 10 But some compounds use tricks Eg: To cross the outer membrane, cations (or polycations) can use self-promoted uptake Locally disrupt the outer membrane to enter the periplasm Efflux will still play a role Crossing the cytoplasmic membrane may be PMFdependent (ΔΨ) Proposed by Bob Hancock in 1984
11 11 EDTA chelates Mg ++, disrupts LPS Mg ++ Mg ++ Mg ++ Lipid A LPS EDTA at 1 mm
12 12 Compounds proposed to cross the OM by Self-promoted uptake Polymyxin B Aminoglycosides [tobramycin] Deglucoteicoplanin-polyamine Azithromycin Merck amino-azalide Merck IMP-inhibitor Trius GyrB/ParE? Rib-X 04 series? At ph 7.4 all are dibasic or more
13 13 Self-promoted uptake by bivalent molecules? Mg++ Mg++ Mg++ Rib-X 04 Local disruption at μm concentrations
14 14 Efflux Most important for P. aeruginosa and other lactose non-fermenters but also for enterics Structural information and computer modeling predicts two rather promiscuous binding sites. Will it be possible to find broad spectrum inhibitors? Or design compounds to avoid efflux?
15 15 Multipronged Problem Rational drug discovery focuses on structural biology of targets For Gram-negative antibacterials, must also study structural biology/chemistry of entry, LPS structure, efflux. But, there is limited structural knowledge for approaching these barriers rationally Multiple parameters must be optimized simultaneously for successful drug design
16 16 For anti-gram negative agents Need robust understanding of entry and efflux requirements There are new Gram-negative agents in the pipeline Rib-X protein synthesis inhibitor Trius dual topoisomerase inhibitor Achaogen LpxC inhibitor [no structure released yet] Improvements in existing classes to specifically overcome pre-existing resistance can and have been made Achaogen - Aminoglycosides Tetraphase - Tetracyclines New β-lactam / β-lactamase inhibitor combinations For all these new agents, entry and efflux as well as target inhibition, were tracked throughout optimization
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