Antibiotic adjuvants – A strategy to unlock bacterial resistance to antibiotics

Abstract

Resistance to available antibiotics in pathogenic bacteria is currently a global challenge since the number of strains that are resistant to multiple types of antibiotics has increased dramatically each year and has spread worldwide. To unlock this problem, the use of an 'antibiotic adjuvant' in combination with an antibiotic is now being exploited. This approach enables us to prolong the lifespan of these life-saving drugs. This digests review provides an overview of the main types of antibiotic adjuvants, the basis of their operation and the remaining issues to be tackled in this field. Particular emphasis is placed on those compounds that are already in clinical development, namely β-lactamase inhibitors.

Eine strukturelle Evaluierung medizinalchemischer Strategien gegen Wirkstoffresistenzen

“…[14][15][16][17] Hier werden wir zwei dieser Entdeckungen hervorheben. Während alle drei Strategien ihre Vor-und Nachteile besitzen, sollte man nicht vergessen, dass auch nach der Entwicklung von Resistenzen durch die Bakterien diese Wirkstoffe noch einen Wert besitzen.…”

“…In jüngster Zeit wurden neue Ansätze entwickelt, um die Resistenz umzukehren und unwirksame Antibiotika wieder zu reaktivieren. [14][15][16][17] Hier werden wir zwei dieser Entdeckungen hervorheben.…”

“…Das erste klinisch zugelassene Medikament wurde ausgehend von einem Anilinochinazolin-Grundgerüst [81] entdeckt und anschließend hinsichtlich der EGFR-Tyrosinkinase-Affinitätu nd Selektivitäto ptimiert. Dies führte zum oral bioverfügbaren Arzneimittel Gefitinib (15,Abbildung 17). [82] Gefitinib zeigt neben der EGFR-Affinität( IC 50 :1n m)a uch Aktivitätgegenüber der Cyclin-G-aktivierten Kinase und der Interleukin-1-Rezeptor-assoziierten Kinase 1(IC 50 :69nm).…”

Reaching toward underexplored targets in antibacterial drug design

“…A few possible approaches to overcome poor bacterial cell penetration have been already suggested (Chopra, ; Hevener et al, ), such as chemical modifications of inhibitors to enhance the uptake (introduction of amino groups, zwitter ions; sterical modifications; Richter et al, ) co‐administration of permeability enhancers (cationic and amphiphilic compounds) and the use of modern approaches in pharmaceutical technology (liposomes and nanoparticles; Bolla et al, ; González‐Bello, ; Benedetto, Kikelj, & Zidar, ; Su et al, ). Another approach which could revive the published Mur enzymes inhibitors is the “ Trojan horse ” strategy where the attachment of siderophores to the inhibitors could employ iron uptake pathways (de Carvalho & Fernandes, ).…”

“…On the other hand, preventing the bacterial efflux is another solution, accomplished by (a) the use of efflux pump inhibitors; (b) modifications that would impair the inhibitor recognition by the efflux pumps; or (c) chemical modifications of inhibitors to achieve irreversible inhibitor binding (González‐Bello, ; Hevener et al, ; Manchester, Buurman, Bisacchi, & McLaughlin, ). The so called “ion trapping” approach, which uses the pH difference between the periplasmic and cytoplasmic space and traps the compounds in the cytosol because of full ionization, might be also effective (Hevener et al, ; Manchester et al, ).…”