Pharmaceutical Approaches to Target Antibiotic Resistance Mechanisms

Abstract

There is urgent need for new therapeutic strategies to fight the global threat of antibiotic resistance. The focus of this Perspective is on chemical agents that target the most common mechanisms of antibiotic resistance such as enzymatic inactivation of antibiotics, changes in cell permeability, and induction/activation of efflux pumps. Here we assess the current landscape and challenges in the treatment of antibiotic resistance mechanisms at both bacterial cell and community levels. We also discuss the potential clinical application of chemical inhibitors of antibiotic resistance mechanisms as add-on treatments for serious drug-resistant infections. Enzymatic inhibitors, such as the derivatives of the β-lactamase inhibitor avibactam, are closer to the clinic than other molecules. For example, MK-7655, in combination with imipenem, is in clinical development for the treatment of infections caused by carbapenem-resistant Enterobacteriaceae and Pseudomonas aeruginosa, which are difficult to treat. In addition, other molecules targeting multidrug-resistance mechanisms, such as efflux pumps, are under development and hold promise for the treatment of multidrug resistant infections.

Efflux pump inhibitors of clinically relevant multidrug resistant bacteria

“…Many promising compounds have been patented, for example, pyranopyridines, peptidomimetics, and indole derivatives . However, no EPI has been clinically approved to date, mainly because of low in vivo efficacy, poor pharmacokinetic properties and/or toxicity problems . There have been some attempts to separate toxicity issues from EPI activity at stages of lead optimization.…”

“…These are peptidomimetic PAβN ( 1 ), pyridopyrimidinone D13‐9001 ( 2 ), pyranopyridine MBX2319 ( 3 ), representatives of the quinoline ( 4 ), and of the indole ( 5 ) derivatives (Figure ). However, only a few EPIs have reached clinical trials, where they have failed due mostly to toxic effects at the concentrations essential for their activity, poor pharmacokinetic properties or low in vivo efficacy . To the best of our knowledge, only for one EPI that has made its way into clinical development, the structure is revealed.…”

New Thiazole Nortopsentin Analogues Inhibit Bacterial Biofilm Formation

“…It is estimated that in the United States alone, more than 2 million people per year are infected by antibiotic-resistant pathogens. Drug-resistant infections lead to about 23,000 deaths in the United States and 25,000 in Europe every year, and the number is higher in developing countries [1,2]. …”

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.…”

“…[85] Die Kaukasier zeigten jedoch keine signifikante Tu morreduktion bei dieser Therapie. Die strukturell ähnlichen EGFR-Inhibitoren Erlotinib (16) [89] und Lapatinib (17) [90] (Abbildung 17), die ebenfalls aus dem Anilinochinazolin-Grundgerüst bestehen, sind weitere Vertreter der ersten Generation und werden gegenwärtig ebenfalls in der Klinik verwendet. [85,87,88] Es wurde später bestätigt, dass Gefitinib eine 100-fach erhçhte Affinitätz u mutiertem Leu858Arg-EGFR im Vergleich zum Wildtyp aufweist, [84] was aber in den antiproliferativen Zelllinienassays nicht gemessen wurde (Tabelle 2).…”