Recent advances in the rational design and optimization of antibacterial agents

Abstract

This review discusses next-generation antibacterial agents developed using rational, or targeted, drug design strategies. The focus of this review is on small-molecule compounds that have been designed to bypass developing bacterial resistance, improve the antibacterial spectrum of activity, and/or to optimize other properties, including physicochemical and pharmacokinetic properties. Agents are discussed that affect known antibacterial targets, such as the bacterial ribosome, nucleic acid binding proteins, and proteins involved in cell-wall biosynthesis; as well as some affecting novel bacterial targets which do not have currently marketed agents. The discussion of the agents focuses on the rational design strategies employed and the synthetic medicinal chemistry and structure-based design techniques utilized by the scientists involved in the discoveries, including such methods as ligand- and structure-based strategies, structure-activity relationship (SAR) expansion strategies, and novel synthetic organic chemistry methods. As such, the discussion is limited to small-molecule therapeutics that have confirmed macromolecular targets and encompasses only a fraction of all antibacterial agents recently approved or in late-stage clinical trials. The antibacterial agents selected have been recently approved for use on the U.S. or European markets or have shown promising results in phase 2 or phase 3 U.S. clinical trials.

Thinking Outside the Box—Novel Antibacterials To Tackle the Resistance Crisis

“…[347] Based on these efforts,t wo novel bacterial topoisomerase inhibitors (NBTIs) are currently in phase II. [349] It is active against Gram-positive pathogens and some commonly important Gram-negative bacteria, such as N. gonorrhoeae,a nd is therefore also studied for the treatment of gonorrhoea. [349] It is active against Gram-positive pathogens and some commonly important Gram-negative bacteria, such as N. gonorrhoeae,a nd is therefore also studied for the treatment of gonorrhoea.…”

“…Gepotidacin (Figure 30) [348] from GSK targets ab inding site which is distinctly different from the fluoroquinolone site. [349] It is active against Gram-positive pathogens and some commonly important Gram-negative bacteria, such as N. gonorrhoeae,a nd is therefore also studied for the treatment of gonorrhoea. [350] Astructurally different motif is found for the…”

Thecloso‐Dodecaborate Dianion Fused with Oxazoles Provides 3D Diboraheterocycles with Selective Antimicrobial Activity

“…[30] For all three compounds, strong bactericidal activity was found in time-kill assays ( Figure 5). [32] Finally,b oron-cage-based compounds 2 should be viewed in the context of "escape from flatland". In line with the trend of personalized medicine, the field of anti-infectived rugs might also benefit from as hift of focus from broad-spectruma ntimicrobials to narrow-spectrum disease-specific antimicrobials.…”

“…[31] It is reasonable to assume that antimicrobial agentsg earedt oward selective microbe-specific targets would have substantial advantages and are ablet os pare the bacteria contributing to health and mitigate the development of resistance. [32] Finally,b oron-cage-based compounds 2 should be viewed in the context of "escape from flatland". [33] This concept underlines the impact that saturation of aromatic heterocycles has on their bioactivity by alteringp arameters,s uch as overall shape, van der Waals volume, polarity,a nd solubility.Ah igher number of saturated carbon atoms leads to ah ighers tructural variety and tunability of properties but at the same time creates stereogenic centers, making selectivea nd straightforward synthesis of ad esired isomer challenging.…”

Über bisherige Denkweisen hinaus – neue Wirkstoffe zur Überwindung der Antibiotika‐Krise

“…[347] Hierauf beruhend befinden sich derzeit zwei innovative bakterielle Topoisomerase-Inhibitoren (NBTIs) in Phase II der klinischen Entwicklung.Gepotidacin (Abbildung 30) [348] von GSK bindet dabei an eine vçllig andere Stelle als die Fluorchinolone. [349] Es weist Aktivität gegenüber Gram-positiven Bakterien auf und ist zudem gegen gemeinhin wichtige Gram-negative Bakterien wie N. gonorrhoeae aktiv,w eswegen die Verbindung derzeit für eine Behandlung von Gonorrhoe untersucht wird. [350] Der NBTI Zoliflodaxin (ETX0941;A bbildung 30) von AstraZeneca weist ein anderes Strukturmotiv auf.D ieses Spiropyrimidintrion besitzt keine Kreuzresistenzen gegenüber Chinolonen und hat ein ähnliches Wirkspektrum wie Gepotida-cin.…”