The Combination of Antibiotic and Non-Antibiotic Compounds Improves Antibiotic Efficacy against Multidrug-Resistant Bacteria

Abstract

Bacterial antibiotic resistance, especially the emergence of multidrug-resistant (MDR) strains, urgently requires the development of effective treatment strategies. It is always of interest to delve into the mechanisms of resistance to current antibiotics and target them to promote the efficacy of existing antibiotics. In recent years, non-antibiotic compounds have played an important auxiliary role in improving the efficacy of antibiotics and promoting the treatment of drug-resistant bacteria. The combination of non-antibiotic compounds with antibiotics is considered a promising strategy against MDR bacteria. In this review, we first briefly summarize the main resistance mechanisms of current antibiotics. In addition, we propose several strategies to enhance antibiotic action based on resistance mechanisms. Then, the research progress of non-antibiotic compounds that can promote antibiotic-resistant bacteria through different mechanisms in recent years is also summarized. Finally, the development prospects and challenges of these non-antibiotic compounds in combination with antibiotics are discussed.

Keywords: antimicrobial mechanism; multidrug-resistant bacteria; non-antibiotic compounds; synergy.

Figure 1

Overview of the molecular mechanisms of antibiotic resistance.

Figure 2

Strategies to enhance the efficacy of antibiotics against resistant bacteria.

Figure 3

The synergistic action between plant-active ingredients and antibiotics: ① inhibit biofilm information; ② disrupt cell membrane; ③ inhibit efflux pumps; ④–⑥ inhibit the synthesis of DNA, proteins, and lipids.

Figure 4

The synergistic action between bacterial metabolites and antibiotics: the combination of metabolites and antibiotics enhances the efficacy of antibiotics because exogenous metabolites stimulate the bacterial TCA cycle and P cycle, resulting in increased bacterial cell respiration, PMF, and ROS.

Figure 5

The underlying synergy mechanisms between AMPs and antibiotics: AMPs change membrane permeability through four membrane destruction mechanisms, including ① aggregate model; ② toroidal pore model; ③ barrel-stave model; ④ carpet model, which induces antibiotics to penetrate into cells, allowing them to reach and interact with targets in bacterial cells. In addition, AMPs block bacterial efflux pumps and increase intracellular antibiotic concentrations, thereby significantly improving the efficacy of conventional antibiotics.

Figure 6

The synergistic action between metal-based NPs and antibiotics. This potential mechanism includes the disruption of the membrane structure, disruption of the electron transport chain, generation of ROS, and disruption of intracellular structures (nucleic acid, proteins, and enzymes).

Figure 7

The synergistic action between phages and antibiotics: ① antibiotic-induced phage production; ② phage-induced penetration of antibiotics into biofilm; ③ phages inhibit efflux pumps to reduce efflux of intracellular antibiotics; ④ phages and antibiotics target different bacterial sites to enhance each other’s effectiveness.