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APPENDIX C GENETICS OF ANTIMICROBIAL RESISTANCE George A. Jacoby1 and K. Brooks Low2 NATURE OF ANTIBIOTIC RESISTANCE Resistance to an antibacterial agent may be either natural or acquired. Some bacterial species are by nature uniformly resistant, some uniformly susceptible, and some include both susceptible and resistant strains. Natural resistance is reflected by gaps in the spectrum of activity of an antibiotic. Thus, broad spectrum drugs such as tetracyclines are effective against many bacterial species while narrow spectrum agents such as polymyxins are active against a restricted group of organisms. Natural resistance (sometimes teemed nonsusceptibility) to a particular antibiotic may be caused by a species' impermeability to an agent or by its lack of a target site, which is present in sus- ceptible species. Acquired resistance develops by mutation or by infection with resistance (R) plasmids. A single mutation may produce a high level of resistance to an antibiotic, such as streptomycin. For other drugs serial passage through gradually increasing concentra- tions of an antibiotic is required, and the resulting resistant strain generally carries multiple mutations, each providing a small increment in resistance. Resistance resulting from mutation is usually specific for the selecting agent or closely related drugs. It is inherited, but is rarely, if ever, spread to other bacteria. 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are likely to be unstable and to revert or be lost due to a disadvanta- geous growth rate when antibiotic selection is withdrawn. In con- trast, acquisition of an R plasmid generally confers resistance to clinically achievable levels of an antibiotic in a single step. A plasmid may carry resistance to one or to many chemically unre- lated drugs. Furthermore, plasmids are transmissible by conjugation, transduction, or transformation to other bacteria and can thus disperse their resistance genes. They generally do not have dele- terious effects on cell growth or virulence and may in fact carry Infectious Disease Unit, Massachusetts General Hospital, Boston, Mass. 2Radiobiology Laboratories, Yale University School of Medicine, New Haven, Conn. 92

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93 genes contributing to v; r'~1 enc*e no w~11 _ _ _ _ ~ _ ~ __ as to antibiotic resistance. 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. How commonly this occurs depends on the par- ticular antibiotic and on the genetic potential for development of resistance. CHROMOSOMALLY DETERMINED RESISTANCE . Chromosomal mutations conferring resistance to antibiotics occur as spontaneous, random, and relatively rare alterations in the DNA composition of bacteria at frequencies of 10 to 10 10 per cell generation. Table 1 lists some well-studied examples of mutational resistance. Further details can be found in reviews by Benveniste and Davis (1973) and Davies and Smith (1978~. The biochemical basis of resistance usually involves one of four mechanisms: the target site is altered so that binding of the anti- hiotic is reduced or eliminated, cell, there is a block in the transport of the drug into the the antibiotic is detoxified or inactivated, or the inhibited step in a metabolic pathway is by-passed. Resistance to the aminoglycosides kasugamycin, neamine, strep- tomycin, or spectinomycin can result from alteration of the amino acid in a specific protein of the 30S ribosomal subunit (Funatsu and Wittmann, 1972; Funatsu et al., 1972; Yaguchi et al., 1976; Yoshikawa _ al., 1975~. Coresistance to neomycin and kanamycin probably in- volves the same mechanism but is less well characterized (Apirion and Schlessinger, 1968) . Ribosomal mutants with broad resistance to aminoglycosides, including gentamicin, kanamycin, neomycin, and tobramycin, also occur, but additional nonribosomal mutations are required to achieve a high level of resistance (Bucker et al., 1977~.

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94 TABLE 1 Mechanisms of Mutational Resistance to Antibiotics Drug Target Aminoglycosides Ribosome. Inhibition of protein synthesis Erythromycin Ribosome. Inh'bition of protein synthesis Nalidixic ac id J)NA gyra se Novobiocin DNA gyrase Penic illins Cell wall biosynthesis Rifampin RNA polymera se Sulfonami de Folic acid biosynthesis Trimethoprim Folic acid biosynthesis Mechanism of resistance Altered ribosomal pro- teixls (kasugamyc'n, 82a; neamine, S17; streptomy- cin, S12; spectinomycin, S5) Altered ribosomal protein ~ gent amicin, kanamycin, neomycin, tobramycin, and others, L6a) Altered 16S RNA methylation (kasugamycin) 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) Altered penic illin-binding proteins Increased synthesis of chromo- s omal bet a-fact ama se Alt ered cel 1 envel ope Altered beta subunit of RNA po lymerase Altered dihydropteroate synthase Thymine au~otrophy s paring folic acid requirement Altered rite osomal protein: S = 30S subunit protein; L = 50S subunit protein.

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95 Some kasugamycin-resistant mutants have altered 16S RNA methyla- tion (Helser et al., 1972~. Lower levels of resistance to aminoglycoside antibiotics can also be attributed to mutations in components of the system by which oxidative energy is coupled to drug transport (Kanner and Gutnick, 1972, Sasarman et al., 1968~. Some aminoglycoside transport mutants are broadly resistant to many other related drugs (Thorbjarnardottir et al., 1978~. Resistance to rifampin develops as a result of an alteration in the beta subunit of its target site, RNA polymerase (Tocchini-Valentini et al., 1968~. 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) by increased synthesis of a chromo- somally determined beta-lactamase, which is normally produced at low levels (Eriksson-Grennberg et al., 1965) or by changes in the cell envelope (Nordstrom et al., 1970~. Mutants that are resistant either to nalidixic acid or to novobiocin can result from alterations in components of DNA gyrase activity (Gellert et al., 1977; Higgins et al., 1978~. Resistance to nalidixic acid can also be caused by altered drug permeability (Bourguignon et al., 1973~. Finally, resistance to sulfonamide can develop from decreased binding by dihydropteroate synthase (Ortiz, 1970), and resistance to trimethoprim can result from mutation to auxotrophy for thymine, thus sparing this impor- tant end-product of folic acid activity (Stacey and Simson, 1965~. Considering the variety of mechanisms that cause mutational resistance of bacteria to antibiotics, it is perhaps surprising that the genetic mechanism is not more common in clinical iso- lates. Mutational resistance is clinically important for nali- dixic acid (Ronald et al., 1966), streptomycin (Finland, 1955), rifampin (Eickhoff, 1971), and trimethoprim (Maskell et al., 1976) and may be responsible for broadly aminoglycoside-resistant clinical isolates (Bryan et al., 1976), but for most drugs plas- mids provide the major source of resistance to antibiotics.

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96 PLASMIDS Plasmids are extrachromosomal genetic elements composed of circular double-stranded DNA. They vary from a molecular weight of approximately 1 million to over 300 million (Hansen and Olsen, 1978~. Hence, they range from one-thousandth to one-tenth the size of the bacterial chromosome and can accommodate from a few to perhaps 500 genes. Essential genes are concerned with plasmid replication and the partitioning of plasmid DNA to daughter cells at the time of bacterial division. Also in this category are genes that deter- mine the number of plasmid copies per cell chromosome and the plasmid incompatibility behavior. In addition to these require- ments, Plasmids may carry other genes. Many Plasmids are infectious or conjugative and possess the genetic machinery for assuring their transmission on contact among bacterial cells by conjugation, a complex process that, for one well-studied plasmid, requires at least 17 genes (Miki et al., 1978~. Plasmids with a molecular weight less than approximately 20 million lack room for this equipment and are generally transfer-deficient (Tra ~ although some Tra plasmids can be transferred ("mobilized") by another conjugative plasmid that is present in the same cell (Clowes, 1972~. A third category of plasmid genes is involved with ~nterac- tions with other replicons and includes genes that inhibit the propagation of certain bacteriophages or the transfer functions of other plasmids. 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) including arsenicals used as feed additives, genes for resistance to physical and chemical agents that damage DNA (Lehrbach et al., 1977), genes for specialized metabolic pathways such as sugar fermentation (Smith et al., 1978) or other catabolic functions (Wheelis, 1975), genes deter- mining bacteriocin production and resistance, and genes involved in pathogenicity such as toxin production or colonization by adherence to mammalian cells. Plasmids can be detected by physical or genetic techniques. Traditionally, plasmid DNA has most often been isolated by cen- trifuging a cell lysate in a cesium chloride density gradient

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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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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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99 containing an intercalating dye such as ethidium bromide that binds differentially to plasmid and chromosomal DNA to allow their separation (Helinski and Clewell, 1971~. Recently, agarose gel electrophoresis has been adapted to allow simpler and more rapid visualization of extrachromosomal DNA (Meyers et al., 1976~. The presence of many plasmids can be demonstrated physically and their molecular weights identified within a day by modifications of this technique (Eckhardt, 1978~. Conjugative plasmids can be detected by testing for transfer of the property they determine to a suitable recipient by mating. Transmission of nonconjugative plasmids can be accomplished by transduction with bacteriophage, transformation with purified plasmid DNA, or mobilization with another plasmid. Finally, certain agents, curing compounds, or physical techniques promote the loss of plasmids or select against plasmid-containing cells. Consequently, they can be used to provide presumptive evidence for the presence of a plasmid- determined characteristic. Further physical and genetic characterization of plasmids is generally necessary to identify and assess the spread of plasmids in epidemiological investigations. Basic physical characteristics are plasmid size, DNA composition as expressed by percent guanine plus cytosine, and the fragmentation pattern produced by restric- tion 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 par- ticular plasmid that is usually, but not always, independent of the host (Causey and Brown, 1978~. Incompatibility behavior is often used to classify plasmids further. Compatible plasmids can coexist in the same host cell while incompatible plasmids cannot and tend to displace each other. By this test plasmids found in enterobacteria can be divided into more than 30 groups (Chabbert et al., 1972; Datta, 1975; Grindley _ al., 1973; Jacob et al., 1977; see Table 3~. Similar incompa- tibility schemes allow Pseudomonas plasmids to be classified into 11 or more groups (Jacoby and Matthew, 1979) and Staphylococcus plasmids to be assigned to at least seven groups (Novick et al., 1977~. Although only a few genes are involved in incompatibility specificity (Palchaudhuri and Maas, 1977), plasmids belonging to the same incompatibility (Inc) group usually share much greater TUNA homology than do plasmids of different Inc groups, thereby reflecting other similarities in gene function (Falkow et al.,

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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), Vir FIV fd, MS2, others R124 FV fd F ~ FVI MS2 Hly-P212 G MS2 Rms149 H1 R27 H2 tncS TP116,pWR23 H3 MIP233 I1 IncI~, IF , Ifl R64,ColIb-~9 Com1 I2 Ifl IPI14, MIP241 (Hly) I3 tnCY If1 R621a, ColIb-[M1420 I4 lncI6 Ifl R721 J R391 R387

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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)1, Ike, R~1 others Q R300B T PilE/81 Rtsl V R753 W PRD 1 R388 X R6K y Phage P1 9 Com9 RIP7 1 From Jacoby and Swartz, in press, wi th pennission. Based on tl~e compila- tion of Jacob _ al. (1977), R. ~. ~rledges (Royal Postgraduate Medical School, London, personal communication, 1979), and other sour`:es. Abbr evi a t io ns: In c, inc ompa t ib i li t y; Com, compat ibili ty . Abbreviations: Col, colicinogenic plasrnid; Ent, enterotoxigenic plasmid; F. fertility plasmid; Rly, hemolysin-producing plasmid; R. resistance plasmid; Vir, the Vi r plasmirl. Some of the plasmids li s ted are me tabolic plasmid.s carryillg genes for sugar utilization, e. g., Plac, FOlac, pWR23, and MIP233.

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102 1974; Grindley _ al., 1973~. Plasmids that are transmissible to _ cold have also been broadly divided into those that inhibit the fertility factor (Fi ~ and those that do not (Fi ~ (Meynell et al., 1968~. Bacteriophage interactions can also be used for plasmid classification. Certain phases, termed donor-specific or male phages (see Table 3), adsorb specifically to surface struc- tures, such as thread-like pill, which are part of the conjugation apparatus for transfer-positive (Tra+) plasmids. Other plasmids characteristically interfere with the propagation of certain phages so that both phage susceptibility and resistance can be used for plasmid classification. PLASMID TRANSFER In the laboratory Tra+ plasmids vary in their transfer fre- quencies from barely detectable values of 10 to 10 to virtually 100X efficiency. Typical average values are 10 to 10 5 per donor. The transfer mechanism of some plasmids is naturally repressed, but is relieved from repression when the plasmid enters a new host (Meynell _ al., 1968~. Other plasmids transfer much more effi- ciently on solid rather than in liquid media. For some plasmids transfer is sensitive to temperature, occurring much more readily at 22 C than at 37C (Rodriguez-Lemoine et al., 1975~. Such plasmids have been responsible for outbreaks of resistant typhoid fever but could have been overlooked had mating experiments been performed at the conventional temperature (Smith et al, 1978~. _ -viva transfer of plasmids appears to be even less efficient than under laboratory conditions, although it has been observed in the gut of both humans and laboratory animals (Smith, 1969 ~ 1970) e A number of factors have been incriminated. Anderson (1974) found that strains containing R plasmids survive less well in the human intestine than do their R counterparts. The anaerobic environment also reduces the fertility of some plasmids (Burman, 1977) as does the presence of bile salts (Wiedemann, 1972) and the metabolic activity of other gut bacteria, especially Bacteroides (Anderson, 1975~. Finally, smooth colony types are less efficient as plasmid recipients than are the rough variants used for laboratory experi- ments (Jarolmen an] Kemp, 1969~. After a volunteer drank a suspen- sion containing 10 donor organisms, Smith (1969) 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. In similar studies with even larger inocula, Anderson et al. (1973a,b) were unable to detect transfer of R plasmids unless specific antibiotics were also

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119 Clowes, R. C. 1972e Molecular structure of bacterial plasmids. Bacterial. Rev. 36:361-405. Dallas, W. S., and S. Falkow. 1979. The molecular nature of heat-labile enterotoxin (LT) of Escherichia colt. Nature 277: 406-407. Datta, N. 1975. Epidemiology and classification of plasmids. Pp. 9-15 in D. Schlessinger, ed. Microbiology--1974. American Society for Microbiology, Washington, D.C. Datta, N., and R. W. Hedges. 1972. Host ranges of R factors. J. Gen. Microbiol. 70:453-460. Datta, N., W. Brumfitt, M. C. Faiers, F. 0rskov, D. S. Reeves, and I. 0rskov. 1971. R factors in Escherichia cold in faeces after oral chemotherapy in general practice. Lancet 1:312-315. Davies, J., and D. I. Smith. 1978. Plasmid-detenmined resistance to antimicrobial agents. Annul Rev. Microbiol. 32:469-518. Davis, C. E., and J. Anandan. 1970. The evolution of R factor. A study of a "preantibiotic" community in Borneo. N. Engl. J. Med. 282:117-122. Del Bene, V. E., M. Rogers, and W. E. Farrar, Jr. 1976. Attempted transfer of antibiotic resistance between Bacteroides and Escherichia colt. J. Gen. Microbiol. 92:384-390. Dunny, G. M., R. A. Craig, R. L. Carron, and D. B. Clewell. 1979. Plasmid transfer in Streptococcus faecalis: Production of . _ multiple sex pheromones by recipients. Plasmid 2:454-465. Echeverria, P., C. V. Ulyangco' Me Te Ho, L. Verhaert' S. Komalarini' F. 0rskov, and I. 0rskov. 1978. Antimicrobial resistance and enterotoxin production among isolates of Escherichia cold in the Far East. Lancet 2:589-592. Eckhardt, T. 1978. A rapid method for the identification of plas- mid desoxyribonucleic acid in bacteria. Plasmid 1:584-588. Eickhoff, T. C. 1971. In-vitro and in-vivo studies of resistance to rifampin in meningococci. J. Infect. Dis. 123:414-420.

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12Q Elwell, L. P., J. De Graaff, D. Seibert, and S. Falkow. 1975. Plasmid-linked ampicillin resistance in Haemophilus influen- zae type b. Infect. Immun. 12:404-410. Elwell, L. P., M. Roberts, L. W. Mayer, and S. Falkow. 1977. Plasmid-mediated beta-lactamase production in Neisseria gonorrhoeae. Antimicrob. Agents Chemother. 11:528-533. Eriksson-Grennberg, K. G., H. G. Boman, J. A. Torbjorn Jans son, and S. Thorn. 1965. Resistance of Escherichia cold to peni- cillins. I. Genetic study of some ampicillin-resistant mutants. J. Bacteriol. 90:54-62. Evans, D. G., R. P. Silver, D. J. Evans, Jr., D. G. Chase, and S. L. Gorbach. 1975. Plasmid-controlled colonization factor associated with virulence in Escherichia cold enterotoxigenic for humans. Infect. Immun. 12:656-667. Falkow, S., P. Guerry, R. W. Hedges, and N. Datta. 1974. Polynu- cleotide sequence relationships among plasmids of the I com- patibility complex. J. Gen. Microbiol. 85:65-76. Finland, M. 1955. Emergence of antibiotic-resistant bacteria. N. Engl. J. Med. 253:909-922, 969-979, 1019-1028. Food and Drug Administration. 1978. Draft Environmental Impact Statement--Subtherapeutic Antibacterial Agents in An~mal Feeds. Bureau of Veterinary Medicine, Food and Drug Admin- istration, Department of Health, Education, and Welfare, Rockville, Md. [371 ~ xviii] pp. Franklin, T. J. 1967. Resistance of Escherichia cold to tetra- cyclines. Changes in permeability to tetracyclines in Escherichia cold bearing transferable resistance factors. G. B. Med. J. 105: 371-378. Funatsu, G., and H. G. Wittmann. 1972. Ribosomal proteins. XXXIII. Location of amino-acid replacements in protein S12 isolated from Escherichia cold mutants resistant to strepto- mycin. J. Mol. Biol. 68:547-550. Funatsu, G., K. Nierhaus, and B. Wittmann-Liebold. 1972. Ribo- somal proteins. XXII. Studies on the altered protein S5 from a spectinomycin-resistant mutant of Escherichia coli. J. Mol. Biol. 64:201-209.

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121 Gardner, P., D. H. Smith, H. Beer? and R. C. Moellering, Jr. 1969. Recovery of resistance (R) factors from a drug-free community. Lancet 2:774-776. Gellert, M., K. Mizuuchi, M. H. O'Dea, T. Itoh, and J. I. Tomizawa. 1977. Nalidixic acid resistance: A second genetic character involved in DNA gyrase activity. Proc. Nat. Acad. Sci. (USA) 74:4772-4776. Grindley, N. D. F., J. N. Grindley, and E. S. Anderson. 1972. R factor compatibility groups. Mol. Gen. Gene t. 119:287-297. Grindley, N. D. F., G. 0. Humphreys, and E. S. Anderson. 1973. Molecular studies of R factor compatibility groups. J. Bac- teriol. 115:387-398. Gyles, C. L., S. Palchaudhuri, and W. K. Maas. 1977. Naturally occurring plasmid carrying genes for enterotoxin production and drug resistance. Science 198:198-199. Hane, M. W. 1971. Some effects of nalidixic acid on conjugation in Escherichia cold K-12. J. Bacteriol. 105:46-56. Hansen, J. B., and R. H. Olsen. 1978. Isolation of large bacterial plasmids and characterization of the P2 incompatibility group plasmids pMG1 and pMG5. J. Bacteriol. 135:227-238. Hedges, R. W., and A. E. Jacob. 1974. Transposition of ampicillin resistance from RP4 to other replicons. Mol. Gen. Gene t. 132: 31-40. Helinski, D. R., and D. B. Clewell. 1971. Circular DNA. Annul Rev. Biochem. 40:899-942. Helser, T. L., J. E. Davies, and J. E. Dahlberg. 1972. Mechanism of kasugamycin resistance in Escherichia coli. Nature (London) New Biol. 235:6-9. Higgins, N. P., C. L. Peebles, A. Sugino, and N. R. Cozzarelli. 1978. Purification of subunits of Escherichia cold DNA gyrase and reconstitution of enzymatic activity. Proc. Nat. Acad. Sci. (USA) 75:1773-1777. Jacob, A. E., and S. J. Hobbs. 1974. Conjugal transfer of plasmid- borne multiple antibiotic resistance in Streptococcus faecalis var. zymogenes. 3. Bacteriol. 117:360-372.

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122 Jacob, A. E., J. A. Shapiro, L. Yamamoto, D. I. Smith, S. N. Cohen, and D. Berg. 1977. Table: Plasmids studied in Escherichia cold and other enteric bacteria. Pp. 607-638 in A. I. Bukhari, J. A. Shapiro, and S. L. Adhya, eds. DNA Insertion Elements, Plasmids, and Episomes. Cold Spring Harbor Laboratory, N.Y. Jacoby, G. A., and M. Matthew. 1979. The distribution of 6-lacta- mase genes on plasmids found in Pseudomonas. Plasmid 2:41-47. Jacoby, G. A., and M. N. Swartz. In press. Plasmids: Microbio- logical and clinical importance in L. Weinstein and B. N. Fields, eds. Seminars in Infectious Diseases, Vol. III. Thieme-Stratton, Inc. N. Y. Jarolmen, H., and G. Kemp. 1969. Association of increased recipient ability for R factors and reduced virulence among variants of Salmonella cholerae~i~ var. kunzendorf. J. Bacteriol. 97:962 Kanner, B. I., and D. L. Gutnick. 1972. Use of neomycin in the isolation of mutants blocked in energy conservation in Escheri- chia colt. J. Bacteriol. 111:287-289. Kleckner, N. 1977. Translocatable elements in procaryotes. Cell 11:11-23. Laufs, R., and F. Kleimann. 1978. [In German; English summary.] Antibiotika-Resistenzfaktoren und andere Plasmide in Bakterien- isolaten von hospitalisierten Patienten. Zentralbl. Bakteriol. Parasitenkd. Infektionskr. Hyg., I. Abt. Orig. Reihe A 240:503- 516. Lehrbach, P., A. H. C. Rung, B. T. O. Lee, and G. A. Jacoby. 1977. Plasmid modification of radiation and chemical-mutagen sensi- tivity in Pseudomonas aeruginosa. J. Gen. Microbial. 98:167-176. Levy, S. B., and L. McMurry. 1978. Probing the expression of plas- mid-mediated tetracycline resistance in Escherichia colt. Pp. 177-180 in D. Schlessinger, ed. Microbiology--1978. American Society for Microbiology, Washington, D.C. Linton, A. H., K. Howe, and A. D. Osborne. 1975. The effects of feeding tetracycline, nitrovin and quindoxin on the drug- resistance of Coli-aerogenes bacteria from calves and pigs. J. Appl. Bacteriol. 38:255-275.

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123 Linton, K. B., P. A. Lee, M. H. Richmond, W. A. Gillespie, A. J. Rowland, and V. N. Baker. 1972. Antibiotic resistance and transmissible it-factors In the intestinal coliform flora of healthy adults and children in an urban and a rural community. J. Hyg., Comb. 70:99-104. Linton, K. B., M. H. Richmond, R. Bevan, and W. A. Gillespie. 1974. Antibiotic resistance and R factors in coliform bacilli isolated from hospital and domestic sewage. J. Med. Microbiol. 7:91-103. Loser, R., P. L. Boquet, R. Roschenthaler, and C. E. N. Saclay. 197' Inhibition of it-factor transfer by levallorphan. Biochem. Biophys. Res. Commun. 45:204-211. Low, K. B., and D. D. Porter. 1978. Modes of gene transfer and recombination in bacteria. Annul Rev. Gene t. 12:249-287. Mahler, I., and H. O. Halvorson. 1977. Transformation of Escheri- chia cold and Bacillus subtilis with a hybrid plasmid molecule. . J. Bacteriol. 131:374-377. Mancini, C., and R. J. Behme. 1977. Transfer of multiple antibio- tic resistance from Bacteroides fragilis to Escherichia colt. J. Infect. Dis. 136:597-600. Mandi, Y., and I. Bela~di. 1974. Effect of rifamycin and its de- rivatives on the transfer of R factor in Escherichia colt. Acta Microbiol. Acad. Sci. Hung. 21:385-389. Mart, I. J. 1968. Incidence of R factors among gram negative bac- teria in drug-free human and animal communities. Nature 220: 1046-1047. Maskell, R., R. H. Payne, and 0. A. Okubadejo. 1976. Thymine- requiring bacteria associated with co-trimoxazole therapy. Lancet 1:834-835. Matthew, M. 1979. Plasmid-mediated 5-lactamases of gram-negative bacteria: Properties and distribution. J. Antimicrob. Chemo- ther. 5:349-358. Matthew, M., and R. W. Hedges. 1976. Analytical isoelectric fo- cusing of R factor-determ~ned 6-lactamases: Correlation with plasmid compatibility. 3. Bacteriol. 125:713-718.

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