Enhanced Antimicrobial Activity through Synergistic Effects of Cold Atmospheric Plasma and Plant Secondary Metabolites: Opportunities and Challenges

Abstract

The emergence of antibiotic resistant microorganisms possesses a great threat to human health and the environment. Considering the exponential increase in the spread of antibiotic resistant microorganisms, it would be prudent to consider the use of alternative antimicrobial agents or therapies. Only a sustainable, sustained, determined, and coordinated international effort will provide the solutions needed for the future. Plant secondary metabolites show bactericidal and bacteriostatic activity similar to that of conventional antibiotics. However, to effectively eliminate infection, secondary metabolites may need to be activated by heat treatment or combined with other therapies. Cold atmospheric plasma therapy is yet another novel approach that has proven antimicrobial effects. In this review, we explore the physiochemical mechanisms that may give rise to the improved antimicrobial activity of secondary metabolites when combined with cold atmospheric plasma therapy.

Keywords: antibiotic resistance; cold atmospheric plasma; secondary metabolites.

Figure 2

Schematic representation of possible structural changes induced by treating γ-terpinene with plasma. (a) represents a possible ring opening mechanism by fission, and (b) represents a possible cleavage at quaternary center. Reproduced with permission from [56] © 1999–2023 John Wiley&Sons.

Figure 1

Different mechanisms involved in antibiotic resilience (a) Modification of the target preventing the antibiotics from combining with the target. (b) Reducing the permeability of cell membrane to reduce the intake of antibiotics. (c) Expulsion of the drugs from cells through efflux pumps. (d) Hydrolyze enzyme inactivating the antibiotics after entering the cell. (e) Metabolic enhancement to limit or alter the sensitivity of the bacteria towards antibiotics. (f) Developing target protective proteins which prevents the antibiotics from attaching to the bacterial target. (g) Initiation of self-repair system. (h) Changing the cell morphology to reduce the antibiotic update. (i) Formation of biofilms or existing as colonies to jointly resist the effect of antibiotics. Reproduced with permission from reference [28] © Zhang, F, et al. 2022 MDPI, Basel, Switzerland.

Figure 3

Potential interactions between terpenoid PSMs and bacterial cells may include the formation of hydrogen and ionic bonds with cell membrane proteins, disruption of membrane integrity, and intracellular interactions with cell components. Reproduced with permission from K. Bazaka et al., 2017 [1]. © IOP Publishing Ltd., 2017.

Figure 4

Schematic representation of the chemical process involved in the peroxide formation. ROS generation near the membrane can target the fatty acyl chain or the head group of phospholipids as well as the side chains of membrane proteins, resulting in the altered function of the bilayer. Reproduced with permission from reference [68] © 2017, American Chemical Society.

Figure 5

Mechanisms of plasma effect on skin permeability. CAP could temporarily downregulate the expression of E-cadherin, which plays a crucial role in the formation of the intracellular junctions. Loss of E-cadherin would damage the tight junctions between the keratinocytes and transiently disrupt the skin barrier function. Reprinted with permission from reference [85] © Controlled Release Society 2020. Published by Spinger.

Figure 6

(a) Secondary metabolite-mediated regulation of multidrug resistance efflux pumps. Secondary metabolites induce the expression of efflux systems, which export the metabolite. The increased expression of efflux pumps can provide collateral resilience to antibiotics used in the clinic by expelling the drugs from the microbial cells. (b) Secondary metabolite interactions with oxidative stress. Schematic depicting how bactericidal antibiotics can cause cell death both by directly disrupting target-specific processes and by indirectly promoting the formation of reactive oxygen species (ROS) as a consequence of altered respiration and cellular damage. Secondary metabolites can interface with these pathways at multiple points, including by interfering with respiration and redox homeostasis, directly generating ROS through redox cycling and detoxifying ROS via one-electron reactions. Secondary metabolites that promote oxidative stress can either antagonize or potentiate antibiotic toxicity, which is likely to depend on whether the resulting increases in ROS are moderate (thin arrow) or severe (thick arrow). Moderate increases in ROS may induce protective oxidative stress responses that can counteract antibiotic toxicity, whereas severe increases in ROS may overwhelm the defenses of the cell, which leads to synergistic effects with bactericidal antibiotics. Reprinted with permission from reference [53] © Springer Nature Limited 2021.