Combination approaches to combat multidrug-resistant bacteria

Abstract

The increasing prevalence of infections caused by multidrug-resistant bacteria is a global health problem that has been exacerbated by the dearth of novel classes of antibiotics entering the clinic over the past 40 years. Herein, we describe recent developments toward combination therapies for the treatment of multidrug-resistant bacterial infections. These efforts include antibiotic-antibiotic combinations, and the development of adjuvants that either directly target resistance mechanisms such as the inhibition of β-lactamase enzymes, or indirectly target resistance by interfering with bacterial signaling pathways such as two-component systems (TCSs). We also discuss screening of libraries of previously approved drugs to identify nonobvious antimicrobial adjuvants.

Figure 1

Combination therapy and traditional adjuvant targets. Wall teichoic acid sysnthesis inhibitors a) tunicamycin and b) ticlopidine, c–h) β-lactamase inhibitors and i–k) efflux pump inhibitors.

Figure 2

Targeting two-component systems. a) The TCS inhibitor RWJ-49815 and b–c) 2-aminoimidazole compounds that suppress antibiotic resistance

Figure 3

a–f) Approved drugs and g–j) compounds identified from high throughput screens that display adjuvant activity