Unraveling the Role of Metals and Organic Acids in Bacterial Antimicrobial Resistance in the Food Chain

Abstract

Antimicrobial resistance (AMR) has a significant impact on human, animal, and environmental health, being spread in diverse settings. Antibiotic misuse and overuse in the food chain are widely recognized as primary drivers of antibiotic-resistant bacteria. However, other antimicrobials, such as metals and organic acids, commonly present in agri-food environments (e.g., in feed, biocides, or as long-term pollutants), may also contribute to this global public health problem, although this remains a debatable topic owing to limited data. This review aims to provide insights into the current role of metals (i.e., copper, arsenic, and mercury) and organic acids in the emergence and spread of AMR in the food chain. Based on a thorough literature review, this study adopts a unique integrative approach, analyzing in detail the known antimicrobial mechanisms of metals and organic acids, as well as the molecular adaptive tolerance strategies developed by diverse bacteria to overcome their action. Additionally, the interplay between the tolerance to metals or organic acids and AMR is explored, with particular focus on co-selection events. Through a comprehensive analysis, this review highlights potential silent drivers of AMR within the food chain and the need for further research at molecular and epidemiological levels across different food contexts worldwide.

Keywords: antibiotic resistance; arsenic; copper; food safety; mercury; organic acids.

Figure 1

Drivers of antimicrobial resistance and their impacts at different levels: humans, terrestrial and aquatic animals, food and feed, crops, water sanitation and hygiene, and the environment (Adapted from [14]). Abbreviations: ARB—Antibiotic-resistant bacteria.

Figure 2

Mechanisms of metal/biocide and antibiotic co-selection: cross-resistance, co-resistance, and co-regulation/co-expression (Adapted from [75]). Abbreviations: R—Resistance, T—Tolerance.

Figure 3

Mechanisms of copper tolerance associated with the pco (A) and sil (B) genes clusters. The genes and their transcriptional and translation directions are indicated below the illustration. Genes with unknown functions are not represented (Adapted with permission from [130]). (License number 5627591056231 attributed by Springer Nature) The figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.

Figure 4

Representation of genes and protein products associated with the tcrYAZB operon and CueO multicopper oxidase protein in Enterococcus spp. The tcrYAZB operon genes and their transcriptional and translation directions are indicated below the illustration (Adapted from [129]). The figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.

Figure 5

Arsenic detoxification and respiratory metabolic pathways in bacteria. Four different systems might be involved in arsenic biotransformation pathways. Inorganic and organic arsenic detoxification pathways include the arsenic resistance efflux system (ars operon) (yellow) and arsenic methylation (green), respectively. The respiratory oxidization of As(III) to As(V) and the reduction of As(V) to As(III) are represented by the Aio/Arx (light pink) and Arr systems (dark pink), respectively. Uptake of As(V) and As(III) is represented by the phosphate transporters (Pit or Pst) and by the aqua-glycerolporins (GlpF) (brown) (Adapted with permission from [183]). Abbreviations: MMAs(III), monomethylarsonous acid; DMAs(III), dimethylarsinous acid; TMAs(III), trimethylarsine. (License number 5627600311910 attributed by Springer Nature). The figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.

Figure 6

Generic model of the bacterial mer operon system. The mer operon genes are indicated below the illustration, with those in parentheses representing genes with variable presence in mer operons. Despite the variability of mer determinants in both Gram-positive and Gram-negative bacteria, overall mer expression is regulated by the MerR protein. The red diamonds represent the different types of Hg (MeHg—methylated Hg, Hg²⁺—inorganic Hg, Hg0—elemental Hg) (Adapted from [215]). The figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.

Figure 7

Bacterial mechanisms for responding to acidic pH stress. The image illustrates some of the best-studied acid response mechanisms used by Gram-negative (A) and Gram-positive (B) bacteria (adapted from [291]). Abbreviations: ADP—adenosine diphosphate, ATP—adenosine triphosphate, Arg—arginine, Agm—agmatine, Cad—cadaverine, GABA—Glu/γ-aminobutyrate acid, Gln—glutamine, Glu—glutamate, Lys—lysine, Orn—ornithine, Putr—putrescine. The figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.