Suppressive drug combinations and their potential to combat antibiotic resistance

Abstract

Antibiotic effectiveness often changes when two or more such drugs are administered simultaneously, and unearthing antibiotic combinations with enhanced efficacy (synergy) has been a longstanding clinical goal. However, antibiotic resistance, which undermines individual drugs, threatens such combined treatments. Remarkably, it has emerged that antibiotic combinations whose combined effect is lower than that of at least one of the individual drugs can slow or even reverse the evolution of resistance. We synthesize and review studies of such so-called “suppressive interactions” in the literature. We examine why these interactions have been largely disregarded in the past, the strategies used to identify them, their mechanistic basis, demonstrations of their potential to reverse the evolution of resistance, and arguments for and against using them in clinical treatment. We suggest future directions for research on these interactions, aiming to expand the basic body of knowledge on suppression and to determine their applicability in the clinic.

Identification of new MmpL3 inhibitors by untargeted and targeted mutant screens defines MmpL3 domains with differential resistance

“…That the FoR for HC2184 was the same as the FoR for HC2149 and HC2169 is interesting as the cross-resistance profiles and results of DiaMOND analysis suggested that these compounds interact differently with MmpL3. While the antagonistic interactions identified by DiaMOND suggest that scaffold combinations may lower the activity of a single inhibitor, antagonistic drug combinations have been proposed to decrease the rate of resistance 42, 43 . It therefore may be possible to design a single inhibitor that fuses more than one scaffold to decrease the rate of resistance.…”

Selenite Cystine Agar for Enumeration of Inoculated Salmonella Serovars Recovered from Stressful Conditions during Antimicrobial Validation Studies

“…Based on the antibiotic disc assay (Table 1), 'on agar' antibiotic resistance was confirmed by growing cultures in TSB (without antibiotics) and plating the cultures on TSA alone, and on TSA containing the chosen antibiotics ( Figure 3). This was done to determine if there was any antagonism that might be at play when multiple antibiotics are added in combination [34][35][36][37]. Based on the antibiotic disc assay (Table 1), 'on agar' antibiotic resistance was confirmed by growing cultures in TSB (without antibiotics) and plating the cultures on TSA alone, and on TSA containing the chosen antibiotics ( Figure 3).…”

Weakest-Link Dynamics Predict Apparent Antibiotic Interactions in a Model Cross-Feeding Community

“…In the United States alone, an estimated 2.8 million antibiotic-resistant infections occur every year ( 1 ). Many previously treatable infections, such as tuberculosis ( 2 ), urinary tract infections ( 3 ), and even Staphylococcus -mediated skin infections ( 4 ) now require higher doses of more powerful antibiotics, and the development of novel antimicrobials is limited ( 5 , 6 ). One potential alternative treatment strategy is the use of drug combinations, which have been used successfully in HIV treatment ( 7 , 8 ) and cancer chemotherapy ( 9 , 10 ).…”