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OCR for page 92
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geous growth rate when antibiotic selection is withdrawn.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.
OCR for page 102
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 37°C (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
OCR for page 119
119
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Representative terms from entire chapter:
escherichia cold
