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Sweet Spot of a Killer PHARMA & LIFE SCIENCES WHITEPAPER Sweet Spot of a Killer ANTIBACTERIAL WARFARE REQUIRES WITS, CREATIVITY AND TIME. In a post-antibiotic era, unicellular organisms are winning an arms race with sheer numbers, high reproductive rates and an acute response to strong selective pressure created by our indiscriminate use of antibacterial drugs. Where to now? CONTENTS A POST-ANTIBIOTIC ERA 3 One view of the future of antibiotics THE ANTIBACTERIAL BATTLEGROUND 4 The obstacles antibacterial drugs must overcome TWO-FOR-ONE TARGET 6 A close look at DNA gyrase and topoisomerase IV OF RINGS, BRIDGES AND POCKETS 7 Antibiotic compound structures and properties A STRONG PUNCH CAN LEAD ASTRAY 9 Balancing strength and solubility AN EASY FIT CAN GO A LONG WAY 11 The potential of improving binding interactions DECOY TO FREE A MOLECULE 13 The role of protein binding THE FEAR OF WATER 16 Hydrophobicity and penetration TIME TO DO THE WORK 17 Finding the sweet spot of effective killers REFERENCES 18 The World Health Organization warned of a potential post-antibiotic era “in which common infections and minor injuries can kill”. “ Finding the balance or ‘sweet A POST-ANTIBIOTIC ERA spot’ that maximizes the amount Since the introduction of the first antibiotics at the beginning of the 20th century, of potent antibacterial agent that we have blasted bacteria infecting our bodies with potent chemicals, only to discover reaches and impacts its target will that they have become resistant to our weapons. We adapt or combine antibiotics to be the maker or breaker of future circumvent this resistance, but the result is often multidrug unresponsiveness. These antibiotic development programs.” unicellular organisms are winning an arms race with sheer numbers, high reproductive rates and an acute response to strong selective pressure created by our indiscriminate use of antibacterial drugs. Now we are running out of defensive options. A combination of financial and political factors has made the development of novel antibiotics a risky investment. Since the beginning of the 21st century, the FDA has approved only seven new chemical entities as systemic antibacterials. Of these, only two have truly novel mechanisms of action that can delay the development of resistance. Acknowledging the dwindling antibiotic arsenal, the World Health Organization has warned of a potential post-antibiotic era “in which common infections and minor injuries can kill”1. Prevailing financial skepticism and an uncertain regulatory environment have clearly contributed to the decreasing number of novel antibiotics introduced into the clinical setting, but the scientific challenge of developing an effective antibacterial is an equally important factor. In a review article on antibacterial discovery, Dr. Lynn Silver points to a discovery void that has seen “no successful discoveries of novel agents since 1987”2. This void is not due to any lack of innovation or effort. Developing novel antibacterials is difficult because potential drug compounds must meet a number of criteria that are not always aligned. 3 THE ANTIBACTERIAL BATTLEGROUND Think about the last time you took an antibiotic. If it Generally, the antibiotic compound must travel from was oral, the pills were probably large and you were the site of administration to the site of infection asked to take them two or more times a day over the via the blood stream or tissue fluid. Blood and course of several days. its derivatives are to a large extent water, so the compound travels best if it is water-soluble. This type of extended, high-dose regimen is essential to achieve the therapeutic goal of killing an evasive Blood also contains a repertoire of proteins, such foreign cell inside of a host made up of drug- as albumin and globulins, that have the ability to susceptible cells. Maintaining high drug levels in bind chemicals. This means that the chances of the the host over an extended period of time to reach antibiotic compound reaching the site of infection and wipe out the culprit bacterial population is and being available to act on bacterial cells are the medical equivalent of ‘shock and awe’ warfare. significantly reduced if it does not dissolve well in Achieving the desired outcome is not a trivial task. water and if it tends to bind to proteins. A brute force Pelting bacteria with insufficient treatment dose or solution to these bioavailability issues is to increase for an insufficient period increases the likelihood that the drug dose – the more compound that enters the an oddball bacterium with a mutation that makes it host, the more that is freely available. However, the resistant to the antibiotic survives the chemical storm host consists of cells that may also be susceptible to and lives to produce other bacteria with the same the compound, so the higher the dose, the greater mutation. Voila! You have a drug-resistant strain of the chance of adverse effects. the pathogen. Once the compound arrives at the site of infection, The development of the antibiotic is also not a trivial it must reach its molecular target within the matter. An antibiotic encounters a number of hurdles bacterium. Unlike the cells of the host, bacteria have on the path from the point of administration to its a cell wall that poses a formidable barrier. Gram- target (Figure 1). All the tricks to overcome these positive bacteria have a cell wall consisting of a obstacles must be incorporated into the chemical thick, extensively cross-linked peptidoglycan layer structure and formulation of the antibiotic. Must enter the bloodstream Potential obstacles Dissolution Ingestion & absorbtion Must travel easily in the for antibiotic bloodstream and avoid binding to proteins treatments IV administration Direct entry Should not enter and adversely aect Site of host cells Must enter infection the body Must cross Gram-negative bacteria outer Must avoid membrane, eux pumps peptidoglycan layer and plasma membrane Must hit target Must cross the thick peptidoglycan Must avoid layer eux pumps and plasma membrane Figure 1. Antibiotics (blue dots) face a number Gram-positive bacteria of potential obstacles on their way from the site of administration to their target within the infecting bacteria. 4 that surrounds the inner cell Gram-negative bacteria produce of bacteria and preventing these membrane and is porous to small a greater variety of enzymes that targets from doing their job. substances. The underlying plasma metabolize antibiotics, such as Some antibiotics punch holes membrane can be penetrated several ß-lactamases, that render into the cell wall of bacteria by via passive diffusion of lipophilic penicillins, cephalosporins, inhibiting the enzymes that make molecules. Unfortunately, monobactams and peptidoglycans. Others inhibit lipophilic molecules are not carbapenems inactive. enzymes to prevent bacteria from very water-soluble, which synthesizing proteins or DNA. brings us back to the hurdle Since the type of proteins of bioavailability. Additionally, regulating molecular traffic is New antibiotic targets are needed membrane-embedded proteins species-specific and the antibiotic to circumvent target-specific called efflux pumps are known to must cross two chemically resistance, which has emerged thwart antibiotics by removing distinct cellular membranes, few against every antibiotic class. them from the cell. antibiotics work against Gram- These new targets can be bacterial negative bacteria. One antibiotic enyzmes or pathways that have Gram-negative bacteria are even class that is effective against never been exploited before, or trickier. Their thin peptidoglycan Gram-negative bacteria, the novel sites of action on currently layer is surrounded by a second fluoroquinolones, passes through exploited targets. Curbing outer membrane that works as the porins of the outer membrane resistance development will an effective barrier between the as a charged, water-soluble require a very careful selection that environment and the periplasm, molecule and then becomes invokes not only new mechanisms the space between the outer uncharged and hydrophobic of action but also enables the and inner cell membranes. in the periplasm, which allows development of multi-target The outer membrane is dotted it to diffuse across the inner monotherapeutic drugs: single with porins that regulate the membrane. This environment- compounds that simultaneously traffic of molecules into and triggered change in molecular impact the function of two or out of the periplasm and can charge illustrates the complexity more targets3. In this way, if act to exclude many antibiotics. of developing effective broad- resistance develops along one line Compared to Gram-positive spectrum antibiotics3. of fire, activity at the other target bacteria, Gram-negative bacteria maintains the efficacy also have a much higher number The final hurdle is hitting the of the antibiotic. and diversity of membrane- target. Antibiotics work by binding embedded efflux pumps. Finally, to essential molecular machinery Inhibit Nucleic Acid Sythesis or Function Folate Inhibit Folate Synthesis Trimethoprim / Sulfamethoxazole Inhibit DNA Gyrase +/- Topoisomerase IV Quinolones Create Free Radicals Metronidazole, Nitrofurantoin Inhibit Cell Wall Sythesis or Function Inhibit Protein Sythesis Beta-Lactams Vancomycin Inhibit 50S subunit Penicillins Daptomycin Macrolides Polypeptides Cephalosporins Clindamycin Carbapenems Linezolid Monobactams Streptogramins 50S Chloramphenicol Inhibit 30S subunit 30S Aminoglycosides Tetracyclines
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