The Effects on Human Health of Subtherapeutic Use of Antimicrobials in Animal Feeds (1980) / Chapter Skim
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Appendix C: Genetics of Antimicrobial Resistance
Appendix C: Genetics of Antimicrobial Resistance
Pages 92-129
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From page 92... ...
While some resistant mutants retain parental growth and virulence, other mutants are partially crippled. Mutants of this type are likely to be unstable and to revert or be lost due to a disadvantageous growth rate when antibiotic selection is withdrawn.
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From page 93... ...
Consequently, while study of mutational resistance to antibiotics has revealed much about normal cellular physiology and the actions of antibacterial agents, the major mechanism for resistance in clinical isolates of bacteria is plasmid carriage. Bacteria with either natural or acquired resistance will be selectively favored in humans, animals, or environments in which antibiotics are used.
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From page 94... ...
Alt ered drug t rans po rt Altered ribosomal proteins (L4, L22) Altered assembly of ribosomal subunits Altered s ubunit of DNA gyras e (nal idixic or oxolinic ac id `Altered drug bans po rt Altered subunit of DNA gyrase (coumermycin A1, novobio cin)
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From page 95... ...
Escherichia cold mutants that are resistant to erythromycin can be selected with alterations in specific ribosomal proteins or in the assembly of the two ribosomal subunits (Pardo and Rosset, 1977; Wittmann _ al., 1973~. Penicillin-resistant mutants can result from alterations of penicillin-binding proteins (Sprat", 1978; Suzuki et al., 1978)
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From page 96... ...
Finally, Plasmids carry genes that effect the host cell's interaction with the environment. Antibiotic resistance genes are the most familiar, but as shown in Table 2 this category also includes genes determining resistance to metallic compounds (Summers and Silver, 1978)
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From page 97... ...
97 TABLE 2 Plasmid-~) etermined Properties Other Than Antibiotic Resistance a Plasmid carrier Gram-negat ive Gram-posit ive Property bacteria bacteria Resistance to metallic compounds Antimony + Arsenic + + Bi smut t, + Boron + Cadmium + Chromiu~r ~+ + Cobalt + Lead + Me rcury + + Nickel + Silver + Tellur ium + Zinc + Res i s tance to age nt s the t damage DNA Alkylating agents + ~ -Irradiat ion + Ultraviolet irradiation + Me t abolic f unct ions Catabolism of camphor, + naphthalene, nicotine, octane, salicylate, or to luene Citrate ut ilization + Fe rmentat ion of lactose, + + raf finose, or sucrose Hemolys in product ion + + Hydrogen sulf ide product ion + Nuclease product ion + Protea se prod~ ct ion + Urease product ion + Bacter~ocin production and + + res i stance
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From page 98... ...
98 TABLE 2 CONT INUED Property Toxin product ion Ent ero toxin Exfoliat ive t ox' n Other factors af fecting virulence Colonization factors K88, K9 9, and ot he rs Colicin V Vir pla smid a + + From Jacoby and Swartz, in press, with permission. _lasmi d carrier Gram-negat ive bacteria Gram-posit ive bacteria +
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From page 99... ...
Basic physical characteristics are plasmid size, DNA composition as expressed by percent guanine plus cytosine, and the fragmentation pattern produced by restriction endonucleases, which are enzymes that recognize specific DNA sequences as cleavage sites (Roberts, 1976~. After endonuclease treatment, the fragments that are produced are separated by agarose gel electrophoresis to produce a characteristic pattern for a particular plasmid that is usually, but not always, independent of the host (Causey and Brown, 1978~.
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From page 100... ...
100 TABLE 3 IncomDatihilT,v Groups for Enteric Plasmids ~ Inc _ tibility ~_ r-specific group designation Syno _ s phage susceptibility Examples A RA4 8 locO, ComlO R16, Co1Ia-K9 C locA-C, Com6 R57b, D fd R711b FI fd, MS2, otbers F R386, ColV, Ent FII fd, MS2, otbers R1, ColB2, Ent FIII fd, others ColB-~98, MIP240 (Hly)
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From page 101... ...
101 TABLE 3 CO NT INUEI) Incompatibility Donor-specific group Synonyms phage susceptibility Examples L R94 bb M IncL, Com7 RIP6 9 N Com2 Il~e, PRDl R4 6 P Com4 PRR1, PRI)
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From page 102... ...
found that few ingested Rob Escherichia cold strains were able to colonize the intestine, that transfer to other E cold occurred rarely, and that these strains persisted for only a few days.
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From page 103... ...
Since plasmid-containing strains, like those sensitive to antibiotics, have variable but finite persistence in the gut flora, continuous administration of antibiotics is more likely to promote plasmid carriage than would intermittent use (Lipton et al., 1975~. PLASMID HOST RANGE An important biological limitation to transfer is plasmid host range, which correlates with plasmid Inc specificity.
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From page 104... ...
PLASMID PREVALENCE Studies of primitive societies little exposed to antibiotics and of bacterial isolates from the preantibiotic era indicate that R plasmids preexisted contemporary antibiotic usage.
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From page 105... ...
105 TABLE 4 Detection of Plasmid-Determined Antibiotic' Resistance in Pathogens a b Antibiotic _ Organism Beta-lactam Cm Gm Km MLS Sm Su Tc Tm Tp Gram-negative Enterobacteriaceae + + + + + + + + + Haemophi lus + + + + inf luenzee Neisseria gonorrhoeae Pseudomonas aerug ino sa Gram-posi tive + + + + + + + + Stachvlococcus + + + + + + + + aureus Staphylococcus + epidermidis . Streptococcus .
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From page 106... ...
found plasmid DNA in 76% of E colt, 31% of Proteus, 95% of Klebsiella pneumonias, 24% of Pseudomonas aeruginosa, 40% of Staphylococcus aureus, and 36X of group D streptococci from clinical sources.
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From page 107... ...
In some cases, multiple resistance seems to be acquired as new resistance genes are incorporated into existing plasmids (Smith et al., 1975~. PLASMID-DETERMINED ANTIBIOTIC RESISTANCE Plasmids determine antibiotic resistance by the same general biochemical strategies discussed previously, but the mechanisms are usually different from those produced by chromosomal mutations.
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From page 108... ...
3-0-Ace t yl tra ns fe r as e Methylation of 23S RNA lIethylation of 23S RNA Subs titute dihydropteroate synthase Diminished uptake Inh ibi tion of intracel lular act ion Substitute di hydrofolate reductase in press, with permission. bAdditional modifying enzymes for aminoglycosides found in Gram-positive bacteria are reviewed by Da~7ies and Smith ( 19 78~.
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From page 109... ...
In a cointegrate plasmid the resistance genes are often clustered together on the it-determinant segment of the plasmid, while the genes for transfer and other basic plasmid functions are clustered on the resistance transfer factor (RTF) segment.
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From page 110... ...
110 TABLE 6 Selected Drug-Resistance Transposons a Molecular 6 Transposon Drug resistance weight (x 10 Tnl Ampicillin 3.2 Tn4 Ampicillin, streptomycin, sulfonamide 13. 6 Tn5 Kanamycin 3.
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From page 111... ...
Multiple plasmids: total level of antibiotic resistance sometimes higher than that due to individual plasmids Genetic rearrangements: Transposition: insertion of R-detenminants from one region of DNA into a new location Fusion: recombination between two plasmids to produce a composite plasmid Disassociation: separation of a plasmid into its component replicons Microevolution: small deletions, insertions, or duplications (Timmis et al., 1978) Gene transfer (reviewed by Low and Porter, 1978~: Conjugation: transfer through cell-to-cell connection of either plasmid or chromosomal TUNA
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From page 112... ...
Commonly, enterotoxin-producing E cold also carry R plasmids, and transfer of resistance often results in concurrent transfer of enterotoxin production (Echeverria et al.
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From page 113... ...
Col V plasmids can carry antibiotic resistance genes. Therefore, as in the case of enterotoxin production, factors that increase the prevalence of R plasmids can also increase the prevalence of virulence factors.
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From page 114... ...
APPLICATIONS AND FUTURE PROSPECTS The variety of mechanisms that bacteria have evolved to deal with antibiotics is impressive, and there is no assurance that new ones will not appear. Plasmids provide microorganisms with a remarkably versatile system for packaging resistance genes, toxin determinants, and other virulence factors in a fond that can be both transmitted from cell to cell and transposed from plasmid to plasmid.
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From page 115... ...
"On the basis of the data reported here, they concluded, 'there hardly seems a need to postulate a veterinary source for the resistant colifonms encountered in the human population.' However, the observed frequency of tetracycline-resistant coliforms in Bristol sewage in 1974 was 3% (Lipton et al., 1974~. It can be argued that the use of other antibiotics to treat humans and the linkage of other antibiotic resistance genes to tetracycline resistance on plasmids account for the discrepancy between 0.757 and 3% or, alternatively, that only 25% of the observed tetracycline resistance can be attributed to the use of antibiotics in humans.
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From page 116... ...
Finally, while the search continues for better antibiotics and combinations that are effective against plasmid-containing strains, attention should also be directed to a search for naturally occurring agents that might directly attack R factor replication or maintenance.
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From page 117... ...
1968. Coresistance to neomycin and kanamycin by mutations in an Escherichia cold locus that affects ribosomes.
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From page 118... ...
1977. Alteration of ribosomal protein L6 in mutants of Escherichia cold resistant to gentamicin.
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From page 119... ...
1978. Antimicrobial resistance and enterotoxin production among isolates of Escherichia cold in the Far East.
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From page 120... ...
1975. Plasmid-controlled colonization factor associated with virulence in Escherichia cold enterotoxigenic for humans.
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From page 121... ...
1971. Some effects of nalidixic acid on conjugation in Escherichia cold K-12.
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From page 122... ...
1977. Table: Plasmids studied in Escherichia cold and other enteric bacteria.
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From page 123... ...
1977. Transformation of Escherichia cold and Bacillus subtilis with a hybrid plasmid molecule.
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From page 124... ...
1970. Resistance of Escherichia cold to penicillins.
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From page 125... ...
1968. Hemin-deficient mutants of Escherichia cold K-12.
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From page 126... ...
1974. Con mutants: Class of mutants in Escherichia cold K-12 lacking a major cell wall protein and defective in conjugation and adsorption of a bacteriophage.
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From page 127... ...
1978. Escherichia cold resistant to ~-lactam antibiotics through a decrease in the affinity of a target for lethality.
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From page 128... ...
1973. Biochemical and genetic studies on two different types of erythromycin resistant mutants of Escherichia cold with altered ribosomal proteins.
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From page 129... ...
1975. A third kasugamycin resistance locus, ksgC, affecting ribosomal protein S2 in Escherichia cold K-12.
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