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Eluding a Post-Antibiotic Era: The Challenge of Designing Novel Antibiotics
Posted on November 13th, 2015 by Thibault Geoui in Pharma R&D
As cases of drug-resistant pathogens multiply, the WHO warns of a “post-antibiotic era.” Designing novel antibiotics, however, remains a scientific challenge because achieving therapeutic efficacy requires painstaking testing of compound properties that often conflict.
Read this excerpt from our white paper, Sweet Spot of a Killer, on leveraging a ‘two-for-one’ target.
Current antibiotics hit a very narrow repertoire of targets (2) and novel ones are hard to find. A good target must have the ability to bind to a producible drug compound, be essential in many bacterial species and not present in the host, and have low potential for cross-resistance, i.e., the mechanism of action must be something bacteria have not yet seen.
During the 1940s and 50s, the golden era of antibiotic discovery, natural products were screened for their ability to prevent the growth of pathogens of interest without much thought about how they worked. Successful candidates were then tested for toxicity in animals. By the late 1970s, the “low-hanging fruit” had been discovered and the need to come up with new compounds using limited resources gave rise to target-oriented discovery methods. Target selection came to have a critical role in the allocation of resources to the screening and development of compounds with antibacterial activity.
In the 1990s, the structure of a truncated subunit of the bacterial enzyme DNA gyrase was determined using x-ray crystallography (4) . This subunit was an ATPase, which binds adenosine triphosphate (ATP) and splits it into adenosine diphosphate (ADP) and phosphate. The energy released in this reaction powers the catalytic activity of gyrase, which prepares DNA for copying by relieving the strain that results from unwinding the double-stranded molecule. Interestingly, the structure was published with a currently unused antibiotic molecule, novobiocin, bound to the ATP binding site. A number of pharmaceutical companies recognized the value of this information: this was a characterized binding site of an essential enzyme, validated to work as a target for an antibiotic. With time and a lot of research, they would expand their sights to include the ATP binding site of a related enzyme, topoisomerase IV (5).
DNA gyrase and topoisomerase IV are present in a broad range of Gram-positive and Gram-negative bacteria, and both have key sequence differences at important sites compared to the human version, topoisomerase II (6). Both bacterial enzymes are essential to DNA replication, but are involved at different points in the process. Finally, both have the same three-dimensional arrangement, with ATPase subunits containing very similar ATP binding sites, called GyrB in gyrase and ParE in topoisomerase IV. This similarity lends itself to the development of a single compound capable of concurrently binding and inhibiting the ATP binding sites of both enzymes: a multi-target monotherapeutic antibacterial.
DNA gyrase and topoisomerase IV are not new targets, just underexploited ones. The fluoroquinolones represent the only currently marketed class of antibiotics that inhibit one or both of these enzymes. The fluoroquinolones inhibit the DNA cleavage and resealing activity of both enzymes by binding to the enzyme activity subunits rather than to the ATPase subunits GyrB and ParE. An older antibiotic class, the aminocoumarins, which includes novobiocin and clorobiocin, bind and inhibit the GyrB subunit of DNA gyrase and (to a lesser extent) the ParE subunit of topoisomerase IV. Clorobiocin was never clinically developed and novobiocin had only limited clinical use after the late 1950s due to rapid resistance development and alleged safety issues. Novobiocin was subsequently withdrawn from the market. Because of its limited use, widespread clinical resistance to antibiotics that target the ATPase subunits of gyrase and topoisomerase IV never had time to develop (7).
According to Dr. Greg Bisacchi, Associate Director and Principle Scientist for Infection Chemistry at AstraZeneca, multiple pharmaceutical companies initiated development programs that screened for compounds or compound fragments that bind to both targets. Taking advantage of the homology between the two ATP binding sites, the low potential for cross-resistance, and the essential nature of these enzymes, these programs aimed to design novel antibiotics with potent activity against Gram-positive and Gram-negative bacteria. As we will see, these programs encountered challenges in balancing antibacterial potency, solubility, and free-fraction (the amount of compound not bound to plasma proteins). Nonetheless, each program has also contributed to an increased understanding of target and compound interaction that in the end has made “a new class of effective and safe antibiotic drugs targeting gyrase and topoisomerase IV […] highly achievable.”
DNA gyrase and topoisomerase IV have very similar structures, consisting of two subunits that cut and rejoin DNA and two subunits that power that function through the hydrolysis (splitting) of ATP. DNA gyrase introduces negative supercoils into the DNA while topoisomerase IV decatenates daughter DNA strands. The homology of the ATP binding sites, the essential function of the two enzymes, and the low potential for cross-resistance development make the ATP binding sites of these two enzymes excellent targets for an antibiotic.
Read the full white paper, Sweet Spot of a Killer, which examines five discovery programs and highlights the difficulty and promise of balancing antibiotic properties.
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