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Journal of Biomedical Research 11(2) : 65-80 (2010)
Antibiotics Resistances: Past, Present and Future
Nabin Rayamajhi, Seung Bin Cha, Han Sang Yoo *
Department of Infectious Diseases, College of Veterinary Medicine,
KRF Zoonotic Disease Priority Research Institute, Brain Korea 21 for Veterinary Science,
Seoul National University, Seoul 151-742, Korea
(Received Jun 3, 2010 / Revised Jun 15, 2010 / Accepted Jun 25, 2010)
ABSTRACT: The discovery of antibiotics has helped to save the lives of an uncountable number of people.
Antibiotics have been grouped in different classes based on their origin, structure, and mechanism of action.
An intrinsic and acquired mechanism of antimicrobial resistance has been identified in many bacterial strains
that are of high clinical importance. This has seriously jeopardized the use of antibiotics and has also caused
the spread of microbes that are resistant to effective first-choice, or “first-line” drugs. Thus, sensible use of
antibiotics and the search for effective alternative measures are of high importance in order to minimize the
effect due to existing and emerging antimicrobial resistant microbes.
Key words: Antibiotics, Antibiotics resistance, Plasmids, Mutation, Beta-lactamases
*Corresponding author: Han Sang Yoo
College of Veterinary Medicine, Seoul National University, San 56-1, Sillim 9 dong, Kwanak-Ku, 151-742 Seoul, Korea
Tel: +82-2-880-1263 Fax: +82-2-874-2738
E-mail: yoohs@snu.ac.kr
66
Nabin Rayamajhi et al.
After the discovery of antibiotic substance
first-choice, or “first-line” drugs [9-15].
penicillin from the fungus Penicillium notatum
in 1928 by Sir Alexander Fleming, antimicrobial
Definition of antibiotics
agents (antibiotics and related medicinal drugs),
It can be defined as any of a large group of chemical
was followed by prontosil, the first sulfa drug, was
substances, as penicillin or streptomycin, produced
discovered in 1935 by German chemist Gerhard
by various microorganisms and fungi, having the
Domagk (1895-1964). Fleming, Florey, and Chain
capacity in dilute solutions to inhibit the growth of
shared the 1945 Nobel Prize for medicine for
or to destroy bacteria and other microorganisms,
their work on penicillin [1-2]. Aminoglycosides,
used chiefly in the treatment of infectious diseases.
chloramphenicol,
macrolides
In other words, it is a drug used to treat infections
were discovered in the year 1950 (Table 1). These
caused by bacteria and other microorganisms.
antibiotics effectively acted on both the Gram
Originally, an antibiotic was a substance produced
tetracycline
and
positive and negative bacteria and were drug of
choice for several bacterial diseases. Later in the
1956 and 1960, vancomycin and methicilin were
discovered that gave breakthrough in treating
infectious disease (Table 1). It is highly effective in
by one microorganism that selectively inhibits the
growth of another. Synthetic antibiotics, usually
chemically related to natural antibiotics, have since
been produced that accomplish comparable tasks.
curing infection particularly due to notorious Gram
positive bacteria. Nalidixic acid was discovered in
the year 1962 and was introduced for clinical use
in 1967 [3]. This is the first synthetic quinolone
antibiotic effective for both the Gram positive
and negative bacteria. These along with its recent
subset of fluoroquinolones are very effectively used
especially in the treatment of urinary tract infections
caused by Gram negative bacteria. Development of
Table 1. Schematic diagram of year and development of
antimicrobial agents
Years Development of antimicrobial agents
1928
Discovery of penicillin
1935
Discovery of sulfonamide
1940
Clinical application of penicillin
1950
Discovery of aminoglycoside, chloramphenicol,
tetracycline and macrolide
first, second and third generation of cephalosporin
in late 90’s added to the armamentarium to fight
1956
Discovery of vancomycin
against infection caused by both Gram positive
1960
Synthesis of methicillin
and
First-generation
1962
Synthesis of nalicixic
cephalosporins are predominantly active against
1967
Development of first generation cephems
negative
bacteria
[3].
Gram-positive bacteria, and successive generations
Development of second generation cephems
have increased activity against Gram-negative
Development of third generation cephems
bacteria [4-8]. These discoveries antimicrobial
agents have saved the lives and eased the suffering
1983
Increased use of third generation cephem,
carbapenem, oral cephem and new quinolone
antimicrobials
of countless numbers of people. However, emerging
antimicrobial resistance in microbes has now
seriously jeopardized its use and has also caused
the spread of microbes that are resistant to effective
Development of carbapenem and monobactam
2000
(Decrese in newly developed antimicrobial
agents)
Antibiotics resistances
Different groups of antimicrobial
67
antibiotics that are bactericidal in action. It’s been
Penicillin G, the most popularly used antibiotic
increasingly used because of their relative safety,
because it is the cheapest, safest, and most effective
their availability both orally and parentrally and
antibacterial treatments available. Penicillin G and
their favorable. 1st generation quinolones (nalidixic
V remains the drugs of choice for treating many
acid) limited to Gram negative enteric bacteria
Gram-positive bacterial infections. Penicillin G
however 2nd and 3rd generation fluoroquinolones
and V are used to treat infections caused by Gram-
(norfloxacin, ciprofloxacin) have Improved activity
positive Staphylococcus pyogenes (strep throat),
against Gram positives e.g. staphylococci and
and Streptococcus pneumoniae (respiratory tract
pneumococci, also has activity against mycoplasma
infections, otitis media) [16]. Methicillin was the first
and legionella [3, 12]. Aminoglycoside Group is
penicillin to have activity against the Staphylococcus
highly active against Gram-negative bacteria, it
strains that were resistant to penicillin G. Ampicillin
is only effective by injection, and is bactericidal.
and amoxicillin have broader spectrum of activity
Streptomycin was the first member of this group to
than earlier penicillins. It is active against common
be used widely, but it has now been largely replaced
Gram-negative bacteria as well as Gram positive
by newer aminoglycosides, such as gentamicin
bacteria. But they are not active against penicillin
[3, 15]. Aminoglycosides group has a potential to
G-resistant staphylococci. Both are effective on
damage the kidneys and cause hearing impairment.
oral administration and are active against the Gram-
Chloramphenicol is a broad-spectrum, orally
negative bacterium Escherichia coli, Haemophilus
effective, bacteriostatic antibiotic. Chloramphenicol
influenzae and Salmonella typhi [1]. Carbenicillin
is an important alternative for treating typhoid fever
was the first penicillin synthesized to possess
and bacterial meningitis because of its ability to
useful activity against Pseudomonas aeruginosa.
penetrate the central nervous system efficiently.
This bacterium is normally only responsible for
The use of these antibiotics in most countries has
infections in hospitalized patients and had proved
declined because of concerns about its ability to
particularly difficult to treat. Cephalosporins are
cause a very rare but fatal anemia and because of
clinically important group of antimicrobial agents.
the availability of other safer drugs. Florfenicol,
Injectable forms of this group are generally broad-
fluorinated chloramphenicol derivative, is a broad
spectrum. The mode of action is bactericidal
spectrum antimicrobial agent active against wide
and that are restricted to hospital use for the
range of Gram positive and negative bacteria [18-
treatment of serious infections [5]. Tetracycline
19].
is bacteriostatic broad-spectrum antibiotic that
has been used to treat a wide range of infections
The antibacterial activity
[17]. Erythromycin (Macrolide group) is a very
Antibiotics targets and impair several essential
safe antibiotic, it is effective orally, bacteriostatic,
mechanisms involved in bacterial metabolism,
and active against Gram-positive infections,
growth or multiplication. It also causes the bacterial
especially those of the respiratory tract caused by
lyses by distortion and damage to the cell membrane
streptococci. For certain patients unable to tolerate
that cause leakage of vital cell materials and death
penicillins, erythromycin has provided a valuable
[1-2, 21-23]. Polymyxins disrupt the bacterial
alternative [14]. Quinolones are broad spectrum
cell membrane by interfering with phospholipids,
68
Nabin Rayamajhi et al.
damaging the osmotic barrier. Resistance to colistin
only efficacious against actively dividing bacteria,
may occur via alteration of the lipid A binding site
since that is when a new cell wall is being created
or by efflux pumps. One possible mechanism for
[1, 8, 11].
colistin dependence may be a mutation of lipid A
By interfering with protein synthesis taking
which results in a defective cell membrane and
place
in
the
ribosome,
several
classes
of
osmotic trauma in the absence of colistin. Inhibition
antimicrobials are able to stop cell division.
of cell wall synthesis by binding to transpeptidases
Certain antimicrobials bind to one or both subunits
and inhibiting peptidoglycan formation is another
(30S, 50S) and cause misreading of the genetic
important mechanism of antibiotic [1, 23]. These
code or formation of abnormal, nonfunctional
transpeptidase enzymes and some other bacterial
protein complexes. Aminoglycosides (gentamicin,
proteins, to which penicillins bind, are collectively
tobramycin, amikacin, streptomycin) act primarily
called penicillin-binding proteins (PBPs). The PBPs
by binding to the 30S subunit. Tetracylines are
are different for Gram-positive and Gram-negative
another biochemical class of antibiotic which also
bacteria and in anaerobic species. β-lactams are
bind to the 30S ribosome [17]. Tetracylines are
Table 2. Some representative antibiotics, their mode of action and mechanisms of resistance
Related research
and references
Cleavage by β-lactamases, ESBLs, 5, 6, 8-11, 37, 38
CTX-mases, Carbapenemases
altered PBPs
Category
Some members Mode of action
β-lactam
Penicillin,
Inhibition of cell wall
Cephalosporins, synthesis
Cefotaximes,
Carbapenems
Aminoglycosides
Streptomycin,
Gentamycin,
Tobramycin,
Amikacin
Inhibition of protein
synthesis
Enzymatic modification, efflux,
ribosomal mutations, 16S rRNA
methylation
Quinolones
Ciprofloxacin,
Ofloxacin,
Norfloxacin
Inhibition of DNA
replication
Efflux, modification, target
mutations
Glycopeptides
Vancomycin
Inhibition of cell wall
synthesis
Altered cell walls, efflux
Tetracyclines
Tetracycline
Inhibition of translation Mainly efflux
Rifamycins
Rifampin
(Rifamycin)
Inhibition of
transcription
Streptogramins
Virginiamycins, Inhibition of cell wall
Quinupristin,
synthesis
Dalfopristin
Enzymatic cleavage, modification,
efflux
Oxazolidinones
Linezolid
Mutations in 23S rRNA genes
followed by gene conversion
Inhibition of formation
of 70S ribosomal
complex
Major mechanisms of resistance
Altered subunit of RNA
polymerase
47, 48, 64
12, 22, 25, 36
15, 22
17, 21, 22, 26
36
22, 26
27, 36, 97
69
Antibiotics resistances
bacteriostatic rather than bactericidal, because their
binding to the ribosome is transient. Several classes
of antimicrobials inhibit the 50S ribosomal subunit.
Resistant
cell wall transpeptidase
Perplasmic space
Beta lactamases
Class A: Serine
Class B: Zinc
Class C: Serine
Class D: Serine
PT
Macrolides (erythromycin), chloramphenicol and
GT
clindamycin are primarily bacteriostatic and attach
reversibly to the 50S subunit and interfere with the
Inner membrane
MexB
linking of amino acids [14, 17, 19, 21, 23].
Inhibition of nucleic acid (DNA) replication
is effectively enhanced by some antimicrobials
Loss of porins
in outer membrane
MexA
(Table 2). They bind to the DNA molecule-gyrase
OprM
complex, inhibiting its function and leading
efflux pumps
to bacterial cell death [12]. Quinolone such as
naladixic acid, which only acts on aerobic Gramnegative species and newer fluoroquinolones, such
Fig. 1. Schematic diagram of antibiotics resistance mechanism.
as ciprofloxicin, norfloxacin, and ofloxacin that have
a much broader spectrum of activity are important
antimicrobial compounds [3, 12, 25]. Bacteria
Gram-negative outer membrane. Efflux pumps can
usually lack the ability to take up folic acid from
actively pump out antibiotics from cells. Gram-
the environment and must synthesize it internally.
negative bacteria resist the activity of tetracyclines
Trimethoprim and the sulfonamides interfere with
by this important mechanism [26].
folate metabolism by competitively blocking the
The antibiotic target may be modified to prevent
synthesis of tetrahydrofolate. Trimethoprim and
the action of the drug: Ribosomes become altered,
sulfonamides are usually administered together
mutated, and chemical-physical changes prevent
because trimethoprim potentiates sulfonamides [2].
antibiotic attachment to those ribosomes. By
synthesis of a new metabolic pathway bacteria
Mechanisms of antimicrobial resistance
can produce a new enzyme that is not inhibited by
Antibiotic resistance is the ability of a bacterium
the antimicrobial. Trimethoprim-sulfamethoxazole
or other microorganism to survive and reproduce
resistance is due to bacteria that produce a
in the presence of antibiotic doses that were
new dihydrofolate reductase not inhibited by
previously thought effective against them. Different
trimethoprim and a new dihydropteroate synthetase
mechanisms are known to enhance the antimicrobial
not susceptible to sulfonamides. Quinolone
resistance (Fig. 1). Microbes could be intrinsically
resistance is affected by point mutations in the
resistant and may lack a target for the antibiotics [5].
DNA gyrase, which prevent binding of the drug to
Chlamydiae do not have peptidoglycan and are not
its target [2, 12, 20, 22, 25-28].
susceptible to the action of penicillins. The antibiotic
target may be inaccessible. Membrane changes
The antibiotic may be chemically modified or
block antibiotic entrance and penetration into the
destroyed
cell. Peptidoglycan in Gram-negative bacteria is
Enzymes degrade antibiotics, or inactivate them
inaccessible to penicillins that cannot penetrate the
by reactions of: phosphorylation, adenylation, or
70
Nabin Rayamajhi et al.
acetylation. Aminoglycoside resistance is largely due
Bacteria may elaborate alternative pathways,
to the alteration of the compound in the periplasmic
avoiding the drug target: Meticillin resistance in
space
acetylate,
meticillin-resistant Staphylococcus aureus results
phosphorylate or adenylate aminoglycosides (Table
from the production of an additional penicillin
2). This alteration of the compound leads to binding
binding protein: PBP2’, which is not susceptible to
to the bacterial ribosomes and poor uptake into
inhibition by penicillins [11, 24].
by
bacterial
enzymes
that
the cell. The genes coding for antibiotics altering
enzymes are often found on transposons and have
Molecular
pumps
energetically
transfer
been identified in members of the Enterobacteriaceae
antibiotics out of the cell: Active efflux is a
and P. aeruginosa, S. pneumoniae and Gram-
mechanism responsible for extrusion of toxic
positive species such as S. aureus, S. faecalis, and
substances and antibiotics outside the cell; this
S. pyogenes. Important examples include the huge
is considered to be a vital part of xenobiotic
range of β-lactamases [5, 11, 13, 23, 26].
metabolism [22]. This mechanism is important in
Chloramphenicol resistance is due to the presence
medicine as it can contribute to bacterial antibiotic
of an intracellular enzyme called chloramphenicol
resistance. Efflux systems function via an energy-
transacetylate. This enzyme acetylates hydroxyl
dependent mechanism (Active transport) to pump
groups on the chloramphenicol structure which
out unwanted toxic substances through specific
causes decreased binding to the 50S ribosome.
efflux pumps. Some efflux systems are drug-specific,
The first florfenicol resistance gene (pp-flo) that
whereas others may accommodate multiple drugs,
confers resistance to both chloramphenicol and
and thus contribute to bacterial multidrug resistance
florfenicol was found to be plasmid encoded from
(MDR) [26].
Photobacterium piscicida. Likewise, flost gene with
97% homology to the pp-flo gene was reported
Antibiotic
Resistance
by
Mutation
and
among Salmonella enterica serovar Typhimurium
Selection: Typical gastrointestinal bacteria divide
DT104. Since then floR gene has been reported in
and multiply quickly, needing only 15-20 minutes to
Escherichia coli and Salmonella spp in plasmid
double by binary fission. The human large intestine
and chromosomal locus as well [18, 19, 30-32].
contains about 100 billion bacteria per gram of solid
Though mode of action of florfenicol is similar to
matter and over 100 different species of bacteria.
chloramphenicol, it is highly effective to variety
Bacteria grow rapidly and mutate rapidly at a rate
of Gram positive and negative clinical bacterial
of 1 in every 100,000 to 1 in every million [12, 36-
isolates. Florfenicol has gained interest as the
38]. Mutations are random events, and typically are
need of alternative microbial agents has become
not caused by antibiotics. When mutations occur,
inevitable to decrease morbidity and mortality due to
biochemical changes often occur. A membrane
emergence of antibiotic-resistance microorganism.
protein, enzyme, or ribosome may be altered. DNA
Description of florfenicol in multi-drug resistance
base pair mutations often translate into single,
Salmonella enterica serovar Typhimurium Phage
different amino acid changes in the protein with
type DT104 worldwide epidemic strains have also
accompanying changes in protein shape, or function,
added its importance from the public health point of
or both. Many potential mutations anywhere along
view [29-35].
a DNA molecule (the basic hereditary material),
Antibiotics resistances
71
increase the chances for development of antibiotic-
microorganisms. Class 1 integron is predominant
resistant bacteria [5, 38-42].
among these serotypes, and is of clinical importance.
This often contains one or more antibiotic resistance
Transfer of Antibiotic Resistance
coding genes in form of cassettes. The gene cassette
DNA and associated traits - such as antibiotic
resides between the 5’ and 3’ conserved segment
resistance - may be transferred between bacteria.
(CS) known as variable region [47]. This functions
DNA transfers may be rare, or fairly common,
as the insertion site for the antibiotic resistance
depending upon circumstances. Large populations
gene cassettes and includes aatC (also known
of closely-related bacteria increase the chances for
as the 59-base element), which participate in the
gene transfer, including resistance genes, which are
recombination mechanism. The 5’-CS of the class 1
among the preferred bacterial gene transfers. The
integron includes an intl1 gene and a promoter PC,
three common gene transfers are:
which directs transcription of the cassettes-encoded
Transformation: Transformation is not an
genes. This has the attI1 primary recombination site
important method of resistance gene transfer. DNA
for integration of resistance gene cassettes. The 5’-
escapes from damaged or dying cells, and live
CS is bound at the inner end by attI1 and the outer
bacterial cells uptake one strand of the genes and
end by IRi, which is a 25-bp sequence that is found
incorporate those into the full DNA gene package.
as an inverted repeat, IRt, at the other end of class
Bacteria can pick up free or “naked” DNA from their
1integron [43-47].
environment by a process called transformation. The
Class 2 integron do not contain the sul1 gene
presence of free DNA is common after cell lysis, but
but in fact include genes whose function promotes
the range of compatibility between the free DNA
Tn7 transposition [47, 48]. The class 3 integron was
and the intact recipient bacteria is narrow.
characterized by the identification of the blaIMP
A transposon is a gene which contains an insertion
gene responsible for broad-spectrum β-lactam
sequence at each end. The insertion sequences
antibiotic resistance [49]. The integrase gene (intl3)
allow the gene to jump to different locations on
demonstrated an identity of 60.9% to the intl1 gene
chromosomal DNA, from plasmid to plasmid
at the amino acid level, with the gene cassettes
or from chromosome to plasmid [43-44]. The
boundaries showing atypical recombination sites
movement of a transposon is called transposition.
[49]. Only Vibrio cholerae is known to have class 4
Transposons are important because they can move
integron to date. This novel class contains the intl4
resistance genes from a non-conjugative plasmid or
gene, which encodes a new integrase which makes
chromosome to a conjugative plasmid, which can
tandem arrays of Vibrio cholerae repeated sequences
then be easily transferred to other bacteria. Another
similar to the arrays of antibiotic resistance gene
genetic element, called an integron, may be located
cassettes found in class 1 integron [47, 48, 49].
on a plasmid or transposon. An integron contains
Integrons can also be physically associated with
one or more resistance genes (called gene cassettes)
other resistance genes, as seen in S. typhimurium
between two conserved DNA regions [34, 44].
DT104. Majority of these strains are characterized
Integron, naturally occurring gene expression
by resistance to at least five drugs including
element, plays an important role in acquisition
ampicillin (A), chloramphenicol (C), streptomycin
and dissemination of antibiotic resistance gene in
(S), sulfonamides (Su) and tetracycline (T) and
72
Nabin Rayamajhi et al.
referred to as ACSSuT-type [34, 36]. These
and multiplies, that gene is maintained and passed
isolates carry two class 1 integrons carrying the
on to all offspring bacteria. Transduction occurs
aadA2, pse-1 and sul1 genes, conferring resistance
when chromosomal or plasmid DNA is transferred
to streptomycin, β-lactams and sulfonamides,
from one bacterium to another by bacteriophages
respectively, which are located close together in the
[58]. Bacteriophages are viruses that attack bacteria.
DT104 chromosomes. floRst, tetR and tetA genes are
Since bacteriophages have a very narrow host
located between two integrons (intervening region)
range, this is a less important method of resistance
of this penta drug resistance genetic locus [13, 44] .
gene transfer which becomes incorporated into the
Florfenicol resistant gene (floRst) confers resistance
host, recipient bacterium. If the bacterium survives
to both chloramphenicol and florfenicol [29, 30].
the infection and multiplies, that gene is maintained
Conjugation: One bacterium attaches to another
and passed on to all offspring bacteria [58-61].
bacterium via a pilus (protein transfer tube) that
transfers a portion of its genes to a receiving
bacterium. Examples are F+ or Hfr bacteria that
Current research
Several
researches
have
been
conducted
transfer to F- bacterium [50]. One, or many genes,
throughout the globe to understand the existing
may be passed in this manner. A plasmid is a circular
and emerging antimicrobial resistance in microbes
body of double stranded DNA which is separate
of different environmental niches (Table 3).
from the chromosome and carries genes that encode
Through the findings of the research it has been
various traits such as virulence and antimicrobial
well understood that antimicrobial resistance
resistance. There are two types of plasmids based
mechanisms are highly influenced by the way
on their ability to transfer from one bacterium to
antibiotics are used locally and because of the
another. Conjugative plasmids can transfer to other
different mechanism discussed above microbes can
bacteria via sex pili, and nonconjugative plasmids
efficiently transfer the resistance either by horizontal
cannot. Cell-to-cell contact is necessary for
or vertical route. Microbes from far geographical
conjugation to occur and both donor and recipient
distance and different unrelated niches have been
end up with a copy of the plasmid. R-factors are
found to have similar mechanism of antimicrobial
plasmids that have traits for both conjugation
resistance. Thus once the resistance mechanism has
and antimicrobial resistance [50]. The transfer of
emerged for any antibiotics, similar mechanism
plasmids by conjugation is an extremely important
can be predicted in other region even at the low or
mechanism because transfer can occur in a broad
short duration of selection pressure imposed by the
range of bacterial species and can extend to highly
use of any antibiotics [9, 10, 62-70]. The resistance
unrelated organisms. A single plasmid can contain
to penicillin emerged in Staphylococcus aureus
genes conferring resistance to multiple classes of
shortly after the discovery and use of penicillin for
antimicrobials [47, 51-57].
therapeutics purpose (1940-1961) [3]. Recently,
Transduction: A virus carries a portion of one
spread of penicillin intermediate and resistant
bacterium’s genes into another bacterium attaches to
clone of Streptococcus pneumoniae has been major
the bacterium, injects viral and some bacterial DNA,
concern in many part of world that emerged during
which becomes incorporated into the host, recipient
1967-1977 (Table 3). Since then several research
bacterium. If the bacterium survives the infection
has been focused in understanding resistance
Antibiotics resistances
mechanism and distribution of resistance clones
and serotype of Streptococcus pneumoniae [70, 71].
Emergence of ESBLs producing Gram-negative
bacilli and VRE was noted during the year 1983
and 1986 [3]. Since then resistance mechanism
cephalosporins and cephamycin has been identified
in microbes from hospital as well as community
acquired infections that are of high clinical concerns
[5, 9, 10, 52-55, 72]. To date, four main classes of
β-lactamases enzymes have been reported in this
group of microbes. Class A are derived from the
older, broad spectrum β-lactamases (eg., TEM-1,
TEM-2, SHV-1) and have an extended substrate
profile that permit hydrolysis of all cephalosporins,
penicillins and aztreonam. These enzymes are
73
Fig. 2. Protein structure of TEM-1 β-lactamase.
most commonly produced by Klebsiella spp. and
Escherichia coli but may be produced by other
Gram-negative bacteria, including Enterobacter,
Table 3. Years indicating the emergence of drug resistance bacteria
Years
Emergence of drug-resistant bacteria
1940-1961
Emergence of penicillinase-producing
Staphylococcus aureus
Emergence and spread of multidrugresistant S. aureus
Salmonella, Proteus and Citrobacter spp. Class
B enzymes contain zinc and are relatively rare.
Class C are plasmid mediated AmpC β-lactamases
developed through the transfer of chromosomal
genes for the inducible AmpC β-lactamases onto
plasmid. Class D β-lactamases are OXA class
enzymes which are uncommon. Chromosomemediated AmpC β-lactamses have been described
1961
Emergence of MRSA
1967
Emergence of PISP
1974
Emergence of penicillinase-producing
H. influenzae
7]. In recent years plasmid mediated ESBLs and
1977
Emergence of PRSP
reported from both the hospital and community
1980
Emergence of BLNAR H. influenzae
acquired infections. AmpC enzymes such as DHA-
1983
Emergence of ESBL-producing Gramnegative bacilli
1 have been found in bacterial species that naturally
1986
Emergence of VRE
K. pneumoniae and Salmonella. Plasmids encoding
1990
Increased infections with MRSA, PRSP,
BLNAR etc.
these AmpC β-lactamases were all derived from the
Increase of registant gonococci
individual representative bacterial species and have
Increase of MDRP
been identified in wide range of microbes [73-79].
2000
Increasse of quinolone-resistant E. coli
in a wide variety of Gram negative bacilli, such as
Pseudomonas aeruginosa and Enterobacter spp [5,
AmpC - types β-lactamases has been increasingly
lack a chromosomal AmpC β-lactamases such as
chromosomally encoded AmpC β-lactamases of
TEM and SHV -ESBLs are class A β-lactamases that
are efficient and clinically important enzymes that
74
Nabin Rayamajhi et al.
play important part in antibiotics resistance (Fig. 2).
Future direction for the research on antimicrobial
SHV-1 activity is similar to that of TEM-1, but it
Based on these information available on
achives better activity against ampicillin. Extended-
antimicrobial compounds and resistance mechanism
spectrum β-lactamases are derived from TEM-1,
of the bacteria it is every evident that antimicrobial
TEM-2 or SHV-1 by mutations that alter the amino
resistance is biological phenomenon that has
acid configurations around the active site of these
existed in the microbes from early evolution and
β-lactamases [7, 75]. Recently, the most successful
would continue till the existence of the microbial
plasmid-encoded β-lactamase in terms of clinical
world. Thus, the most rational approach would
significance are members of the CTX-M families.
be minimizing and optimum use of antimicrobial
These β-lactamases inactivate the β-lactam
compounds that would help to control the emergence
antibiotics by catalyzing their hydrolysis. Like
of resistant bacteria. Alternate approaches like
TEM and SHV enzymes, in response to clinical use
probiotics and vaccine have been effective in
of extended-spectrum β-lactam antibiotics, natural
prevention of infectious diseases [89, 90]. Likewise,
occurring variants of CTX-M has been isolated
bacteriophages or “phages” that disrupt bacterial
like that contain amino acid substitutions that alter
metabolism and cause the bacterium to lyse could
the enzyme’s substrate specificity [5, 9, 76, 78-
be another therapeutic option. Several reports on
79]. Some of the new variants exhibited increased
therapeutic use of lytic bacteriophages to treat
activity (Kcat/Km) against the extended-spectrum
pathogenic bacterial infections are made available
antibiotics without losing their activity against
for future research. Phage therapy may prove as
penicillin [6, 80-84].
an important alternative to antibiotics for treating
Likewise, resistance microbes to antibiotics
multidrug resistant pathogens [91-93]. Similarly,
used in both the hospitals and farms have been
researches on antimicrobial peptides have also
identified from the animals of farm origin. Many
shown that these components of innate immunity
research has been focused on the surveillance and
are potent, broad spectrum antibiotics which
monitoring the use of antibiotics in farms as it
demonstrate potential as novel therapeutic agents.
can serve as reservoir and facilitate the spread of
These peptides can act on both Gram negative and
multidrug resistant microbes and its determinants
Gram positive bacteria, including mycobacteria,
to environment. Especially the comparative study
Mycobacterium tuberculosis, enveloped viruses,
of phenotype and genetic resistance mechanism
fungi and even transformed or cancerous cells. It may
in microbes from farm and human origin would
also be useful in enhancing immunity by functioning
be helpful to get insight into the existing situation
as immunomodulators [94, 96]. Development of new
of local selection pressure imposed by the use of
drugs by making use of bioactive phytochemicals
antibiotics agents both in humans and animals.
and plants have an almost limitless ability to
Because of the emerging resistances and its impact
synthesize aromatic substances are targets of several
on public health, use of antibiotics in animal has
ongoing research. Most of these compounds are
been long debated and different preventive majors
phenols or their oxygen-substituted derivatives such
are being practiced to minimize the effect due to the
as tannins. In many cases, these substances serve
use of antimicrobials in animal farms [67, 68, 70,
as plant defense mechanisms against predation by
73, 74, 85-88].
microorganisms,insects, and herbivores. Many of
Antibiotics resistances
the herbs and spices used by humans to season food
yield useful medicinal compounds including those
having antibacterial activity [97-99]. One of the
major causes of antibiotic resistance is the decrease
of effective drug concentration at their target place,
due to the increased action of ABC transporters.
Since ABC transporter blockers can be used in
combination with current drugs to increase their
effective intracellular concentration, the possible
impact of ABC transporter inhibitors is of great
clinical interest. ABC transporter blockers that may
be useful to increase the efficacy of current drugs
have entered clinical trials and are available to be
used in therapeutic regimes [99-101].
Acknowledgements
This work was supported by a grant funded by
the Korean Research Foundation (KRF-200621-E00011, KRF-2006-005-J502901), a BK-21
grant, and a Bio-Green 21 grant (20070401-034009-007-01-00).
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