2016
DOI: 10.1039/c6md00232c
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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, an… Show more

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Cited by 20 publications
(19 citation statements)
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“…[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.…”
Section: Novel Bacterial Topoisomerase Inhibitorsmentioning
confidence: 99%
See 1 more Smart Citation
“…[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.…”
Section: Novel Bacterial Topoisomerase Inhibitorsmentioning
confidence: 99%
“…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…”
Section: Novel Bacterial Topoisomerase Inhibitorsmentioning
confidence: 99%
“…[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.…”
Section: Additionaltransformations and Mechanistic Proposalmentioning
confidence: 99%
“…[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.…”
Section: Additionaltransformations and Mechanistic Proposalmentioning
confidence: 99%
“…[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.…”
Section: Fluorchinoloneunclassified