Abstract
Antibiotic resistance poses a tremendous threat to human health. To overcome this problem, it is essential to know the mechanism of antibiotic resistance in antibiotic-producing and pathogenic bacteria. This paper deals with this problem from four points of view. First, the antibiotic resistance genes in producers are discussed related to their biosynthesis. Most resistance genes are present within the biosynthetic gene clusters, but some genes such as paromomycin acetyltransferases are located far outside the gene cluster. Second, when the antibiotic resistance genes in pathogens are compared with those in the producers, resistance mechanisms have dependency on antibiotic classes, and, in addition, new types of resistance mechanisms such as Eis aminoglycoside acetyltransferase and self-sacrifice proteins in enediyne antibiotics emerge in pathogens. Third, the relationships of the resistance genes between producers and pathogens are reevaluated at their amino acid sequence as well as nucleotide sequence levels. Pathogenic bacteria possess other resistance mechanisms than those in antibiotic producers. In addition, resistance mechanisms are little different between early stage of antibiotic use and the present time, e.g., β-lactam resistance in Staphylococcus aureus. Lastly, guanine + cytosine (GC) barrier in gene transfer to pathogenic bacteria is considered. Now, the resistance genes constitute resistome composed of complicated mixture from divergent environments.
Highlights
The introduction of antibiotics once reduced human morbidity and mortality caused by infectious diseases dramatically
Together with the fact that similar functional proteins distribute in a wide range of phyla/biosphere irrespective of the large difference of guanine + cytosine (GC) contents in genomes, e.g., Erm-like protein is present in Yuhushiella deserti (GB No SFO87742, E value = 3e-130) as well as Homo sapiens (GB No.NP_001335005, E value = 4e-19), these results indicate that the antibiotic producing bacteria have evolved the resistant systems from the accidentally acquired related genes within the biosynthetic gene clusters
VanHAX enzymes together with two component regulatory system VanSR are implicated in the resistance and regulatory mechanisms in vancomycin-resistant Enterococci (VRE) by redirecting a portion of the peptidoglycan biosynthetic pathway, whereas vanSR genes are missing in the DNA flanking the vanHAX cluster in balhimycin producer, and vanHAX genes are constitutively expressed [251,252]
Summary
The introduction of antibiotics once reduced human morbidity and mortality caused by infectious diseases dramatically. Human morbidity and mortality by tuberculosis were greatly reduced after the introduction of streptomycin and kanamycin. Antibiotic resistance is mainly due to efflux of antibiotics by transporters, prevention of interaction of antibiotics with target by mutation, modification and protection of target, and modification of antibiotics. These mechanisms result from the inherent structural or functional resistant characteristics, the acquired resistance by mutational change or horizontal gene transfer, and the adaptive antibiotic resistance [2,3,4]. The relationships of the resistance genes between producing bacteria and pathogenic bacteria are reevaluated again at their amino acid sequence as well as nucleotide sequence levels
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