Comparison of Strategies to Overcome Drug Resistance: Learning from Various Kingdoms

Abstract

Drug resistance, especially antibiotic resistance, is a growing threat to human health. To overcome this problem, it is significant to know precisely the mechanisms of drug resistance and/or self-resistance in various kingdoms, from bacteria through plants to animals, once more. This review compares the molecular mechanisms of the resistance against phycotoxins, toxins from marine and terrestrial animals, plants and fungi, and antibiotics. The results reveal that each kingdom possesses the characteristic features. The main mechanisms in each kingdom are transporters/efflux pumps in phycotoxins, mutation and modification of targets and sequestration in marine and terrestrial animal toxins, ABC transporters and sequestration in plant toxins, transporters in fungal toxins, and various or mixed mechanisms in antibiotics. Antibiotic producers in particular make tremendous efforts for avoiding suicide, and are more flexible and adaptable to the changes of environments. With these features in mind, potential alternative strategies to overcome these resistance problems are discussed. This paper will provide clues for solving the issues of drug resistance.

Keywords: antibiotic resistance; bacterium; drug resistance; fungus; marine animal; phycotoxin; plant; self-resistance; terrestrial animal.

Figure 1

(A) Construction of human voltage-gated sodium channel 1.4. (B) Comparison of amino acid residues of human Nav1.4, human Nav1.5, Fugu Nav1.4a, Tetraodon Nav1.4a, and Mya arenaria Nav. The amino acid numbering is according to that of human Nav1.4. The GenBank accession numbers are human Nav1.4: P35499; human Nav1.5: Q14524; fugu Nav1.4a: ABB29441; Tetraodon Nav1.4a: ABB29443; and Mya arenaria Nav: AAX14719. The amino acids in alanine (A) in DIV (DEKA) are marked with red, those in two aspartate residues in DIII and DIV (EEDD) are marked with light blue, and the amino acid residues at 407 are marked with dark blue.

Figure 2

(A) Amino acid sequence of α-bungarotoxin (GenBank accession No. P01378). Amino acids involved in the binding to thr acetylcholine receptor are marked with bold red. Red underlines indicate loop II and loop III, respectively. (B) Comparison of amino acid sequences of human α2-acetylcholine receptor (GenBank accession No. CAD89000) and Torpedo marmorata α-acetylcholine receptor (GenBank accession No. AAA96704). Amino acid residues involved in the ligand-binding are marked with bold red. Wavy red underlines show the trans-membrane regions. (C). Comparison of critical amino acid residues of acetylcholine receptors from species that are sensitive or resistant to α-bungarotoxin. Dots indicate the same amino acid residues as that of a mouse.

Figure 3

Comparison of amino acid sequences in site 3 of the human sodium channels and that of Haplopelma schmidti (OhNav1). The critical residues are marked with blue and red. The amino acid numbering is according to OhNav1.

Figure 4

Comparison of the amino acid sequences of CPT is of the CPT-producing and CPT-nonproducing plants and humans. Ophiorrhiza liukiuensis, Camptotheca acuminate, and Ophiorrhiza pumila are CPT-producing plants, while Ophiorrhiza japonica and Homo sapiens are nonproducing. GenBank accession numbers are BAG31374, BAG31376, BAG31373, BAG31375, and AAA61206, respectively. The critical amino acid residues for the resistance (aspragine and serine) were marked with red.

Figure 5

Comparison of amino acid residues of three isoforms of Oncopeltus fasciatus Na⁺/K⁺-ATPases, and those of Drosophila melanogaster and Homo sapiens. The critical residues are marked with red. GenBank accession numbers are AFU25689, AFU25688, AFU25687, AAC05260, and NP_000692, respectively. The critical amino acid residues for the binding of ouabain were marked with red.

Figure 6

The relationship between predators and prey, and herbivores and plant.