Mechanisms of Antibiotics Resistance in Bacteria

Abstract

The resistance is determining a growing hug issue in health fields worldwide, where the bacterial cells possessed the ability to resist the old antibiotics as well as the newly discovered antibiotics through several capabilities and mechanisms, including the natural, acquired and cross ones, this paper will highlight most of the antibiotics and the mechanics of resistance.

Full text

Sys Rev Pharm 2020; 11(6): 817 823
A multifaceted review journal in the field of pharmacy
E-ISSN 0976-2779 P-ISSN 0975-8453
817 Systematic Review Pharmacy Vol 11, Issue 6, 2020
Mechanisms of Antibiotics Resistance in Bacteria
Thualfakar Hayder Hasan1*, Raad A. Al-Harmoosh1,2
1Department of Medical Laboratories Techniques; Altoosi University College, Najaf, Iraq.
2College of Science; University of Kufa, Najaf, Iraq.
E-mail: thualfakar@altoosi.edu.iq, raad.alharmoosh@altoosi.edu.iq
Article History: Submitted: 13.04.2020 Revised: 17.05.2020 Accepted: 24.06.2020
ABSTRACT
The resistance is determining a growing hug issue in health fields
worldwide, where the bacterial cells possessed the ability to resist the
old antibiotics as well as the newly discovered antibiotics through
several capabilities and mechanisms, including the natural, acquired
and cross ones, this paper will highlight most of the antibiotics and the
mechanics of resistance.
Keywords: Resistance, Antibiotics, Bacteria, QRDRs, Efflux pumps
Correspondence:
Thualfakar Hayder Hasan
Department of Medical Laboratories Techniques, Altoosi University
College, Najaf, Iraq
E-mail: thulafakar@altoosi.edu.iq
DOI: 10.31838/srp.2020.6.118
@Advanced Scientific Research. All rights reserved
INTRODUCTION
Bacterial resistance is the capability of bacterial cells to
prevent antibiotic bacteriostatic or bactericidal effects [1].
The excessive and unintended usage of antibiotics
contributes to resistance development in bacteria [2].
Because of the extensive uptake, the evolvement
of microorganisms resistant with the time and problems
have arisen with these resistant microorganisms for the
treatment of certain infections [3]. Nowadays, resistance is
determining as a big issue in the path of new drug synthesis,
developing antibiotic resistance is a major public health
problem worldwide [4].
The four principal forms of antibiotic resistance evolve as
1- Natural resistance (Intrinsic, Structural)
In this type of resistance, the usage of antibiotics is not
associated with the resistance but it caused by the bacteria's
structural properties [5]. This occurs as a result of intrinsic
resistance, or microorganism which doesn't follow the target
antibiotic structure, or antibiotics which due to its
characteristics do not encounter its target [6]. Gram-
negative bacteria and vancomycin, for example, vancomycin
antibiotics does not move through the outer membrane soo
that these Gram-negative bacteria are naturally insusceptible
to vancomycino[7].
Likewise, L-form bacteria that are cell wall-less types of the
bacteria, such a Ureaplasma and Mycoplasma Mycoplasma
that are naturally owning beta-lactam antibiotics resistance
[8].
2. Acquired resistance
Regardless of resistance development due to alteration in
the genetic features of bacteria, an acquired because it is not
affected by the antibiotics it was previously susceptible to it
[9]. This form of resistance comes from the main
chromosome or extra chromosome structures (plasmids,
transposons, etc.) [10].
Chromosomal resistance results from mutations that change
randomly bacterial chromosome, these mutations can occur
by certain physical and chemical factors [11].
This may be due to changes in the composition of bacterial
cells, so that may be decreased bacterial drug permeability,
or maybe changes to the drug's target in the cell [12].
Streptomycin, aminoglycosides,o erythromycin,o, and
lincomycin can develop resistance to these forms [13].
Extrachromosomal resistance relies on extrachromosomal
genetic materials that can be transmitted via plasmids,
transposons, and integrons [14]. Plasmidsoareosegments of
DNAothatocanoreplicateoindependentlyoof chromosomal
DNA [15]. A plasmid is typically responsible for the
development of antibiotic inactive enzymes [16].
There are main forms of holding genetic material (resistance
genes and plasmids) from bacterial cells, this form are
transduction, transformation, conjugation, and mechanism
of transposition [17].
The genes with antibiotic resistance on the chromosome or
plasmid are intertwined and are situated at the beginning
with different integration groups, or integrons.
Recombination is very normal in integrons [18].
3. Cross-resistance
It is mean the resistance to a specific antibiotic by specific
microorganisms, that work with the identical or related
mechanisms and that are also resistant to other antibiotics
[19]. This is generally seen when antibiotics have common
structures: such as resistance to erythromycin,neomycin-
kanamycin, or resistance to cephalosporins and penicillins
[20].
However, cross-resistance can some times be seen in a
completely distinct group of drugs as well, like a cross-
resistance that exists amongst erythromycin-lincomycin,
this resistance might be the chromosomal origin or not [21].
4. Multi-drug and other types of resistance
Multidrug-resistant species are typically pathogens that
have been resistant to their antibiotics, this ensures that the
bacteria will no longer be eliminated or regulated by a single
drug [22]. Inappropriate utilization of antibiotics
for treatment culminated in the introduction of multidrug-
resistant pathogenic bacteria [23]. Either of the two
mechanisms can induce multidrug resistance in bacteria
[24].
Firstly, these bacteria will acquire several genes, each coding
for specific drug resistance, this form of resistance usually
exists on R-plasmids [25].
Secondly, the form of multidrug resistance may also occur
by enhanced gene expression encoding for efflux pumps,
enzymatic inactivation for antibiotics, changes in target
structure, and others [26].

Thualfakar Hayder Hasan et al / Mechanisms of Antibiotics Resistance in Bacteria
818 Systematic Review Pharmacy Vol 11, Issue 6, 2020
If the bacterial strains are not susceptible to three or more
antimicrobial types, they are called multidrug-resistant
(MDR) bacteria. If the species, resistant to all but one or two
classes of antibiotics, are deemed highly resistant to
medicines, whether the species resistant to all usable
antibiotics are known as pan-drug resistant [27,28].
For example, Acinetobacter species with multidrug
resistance (MDR) can be identified as the bacteria that
having the resistant ability to at least three groups of
antibiotics classes, for example for all penicillin and
cephalosporin, aminoglycosides and quinolones groups
[29].
Extensive Acinetobacter spp., drug-resistant (XDR), isolate
resistant to the three types of antibiotics classes mentioned
above in (MDR), and even carbapenem-resistant,
Acinetobacter spp. , Pandrug resistant, or pan-resistant
(PDR), these bacteria can be going to be the XDR as well as
polymyxin-resistant and tigecycline resistance [30,31].
Mechanisms of Antibiotics Resistance
A-The modifications
Modifications that happen in the drug-related receptor and
the location of the target regions of the relation with the
antibiotics are distinct, these can be complex enzymes and
ribosomes [32]. The most frequently identified resistance
consistent with variations in the ribosomal target is in
macrolide antibiotics [33]. The most popular examples here
are the evolvement of penicillin resistance due to the
mutations of penicillin-binding proteins beta-lactamase
enzymes in Staphylococcus aureus, Streptococcus
pneumoniae, Neisseria meningitides, and Enterococcus
faecium strains [34].
B.i Enzymatic inactivation of antibiotics
Most of the bacteria synthesize antibiotic degrading
enzymes, the enzymatic inactivation mechanism is one of
the most important antibiotics resistance mechanisms [35].
In this group, beta-lactamases, aminoglycosidase,
chloramphenicol, and erythromycin modifying enzymes are
the most popular examples [36].
C. Reduction of the inner and outer membrane
permeability
This mechanism results from changes in the permeability of
the internal and external membrane so that decreased drug
uptake into the cell or rapidly ejected from the pump
systems [37]. Due to a decrease in membrane permeability
as a result of porin mutations that may occur in proteins of
resistant strains for example; a mutation in specific porins
called OprD can cause resistance to carbapenem in
Pseudomonas aeruginosa strain [38]. Reduction in outer
membrane permeability can play an important role in
quinolone resistance and aminoglycoside resistance [39].
D. Active Pumps System
Resistance develops most commonly in the tetracycline
group of antibiotics via the active pump systems [40]. With
an energy-dependent active pumping system, tetracyclines
are thrown out and cannot concentrate within the cell[41].
Thisomechanismooforesistanceoisoinoplasmidoandochrom
osomalocontrol.oActive pumping systems for example are
effective in resisting quinolones,o14-membered
macrolides,ochloramphenicoloandobeta-lactamso[42].
E.oUsingoanoalternativeometabolicopathway
Unlikeosomeoofotheotargetoalterationsoinobacteria, the
latest drug-susceptible pathway eliminates the need for
objective development [43]. Bacteria can prepare folic acid
from the environment, rather than synthesizing folic acid so
that it becomes resistant among sulfonamide and
trimethoprim [44].
ResistanceobyoAntibioticsogroupoMechanisms
A. Beta-lactams Resistance
Antibiotics of beta-lactam are a wide class of antibiotics,
including penicillins, cephalosporins, monobactams, and
carbapenems [45]. Synthesis of beta-lactamase enzymes is
the most common resistance mechanism here [46].
1- Beta-lactamase Enzymes
At the molecular level, there are 4 groups (A, B, C, D)of
beta-lactamase enzymeso[47]. Beta-lactamases A, C, and D
that deferent from B-class that function cool ester enzymes
mediated, while the latest was need zinc ion as
metalloenzyme [48].
Beta-lactamases Class A
These resistances occur in both Gram-positive and Gram-
negative bacteria and mostly mediated by plasmid or
transposon. Capable usually of being inducible [48]. This
group includes the gram-negative bacteria TEM, SHV,
ESBL. ESBL primarily occurs in E. coli and Klebsiella
pneumoniae [49].
Beta-lactamases Class B
Bacteroides fragilis, observable species of Aeromonas and
Legionella, enzymes that hydrolyze carbapenems, penicillin,
and cephalosporins [50].
Beta-lactamases Class C
Generally seen in Gram-negative bacteria and chromosome-
localized (Group I, AmpC, etc.) [51]. This resistance
mechanism is not inhibited by clavulanic acid and has an
inducible characteristic so produced in high levels in the
presence of beta-lactam antibiotics [52]. Often known as
Inducibleo Beta-Lactamaseso(IBL), they found in
Enterobacterocloacae,oCitrobacterofreundii,oSerratiaomarce
scens, and P. aeruginosa [53].
Beta-lactamases Class D
These enzymes are induced by beta-lactamases antibiotics
and produced in Gram-positive cocci such as Staphylococcus
aureus so that degrade Oxacillin [53].
2. Modifications in Penicillin-Binding Proteins (PBP)
Penicillin-binding proteins (PBP) in peptidoglycan
synthesis in the bac responsible for the Antibiotic target of
beta-lactam, Carboxypeptidase PBPs, and the enzymes of

Thualfakar Hayder Hasan et al / Mechanisms of Antibiotics Resistance in Bacteria
819 Systematic Review Pharmacy Vol 11, Issue 6, 2020
transpeptidase PBP is the most common in gram-positive
bacteria, due to changes in it, resistance results in [54].
Methicillin-resistant S. aureus (MRSA) is willing to take
responsibility for methicillin resistance in strains, mecA
gene, this gene results in PBP-2a synthesis enhancing beta-
lactam antibiotic resistance [55]. The modifications in S.
pneumoniae in PBP 2b are responsible for the resistance to
penicillin and cephalosporin [56].
3. Modifications in Proteins of the membrane
Change in the porin channels in gram-negative bacteria,o
for example, P. aeruginosa with a devoted channel protein
registered in OprD may evolve carbapenem resistance [57].
Antibiotic accumulation can be prevented in the active
pump systems cell. Consequently, the group of beta-lactams,
tetracyclines, chloramphenicol, and quinolones can lead to
resistance [58].
B. Antibiotics Resistance of Aminoglycoside Group
1. Aminoglycosides Modifying Enzymes
The most important mechanism for the emergence of
resistance to aminoglycosides in aerobic gram-negative
bacteria is enzymatic inactivation. Enzyme modifying has a
major role in resistance to aminoglycosides [59]. These
enzymes are often of plasmid or transposon origin, there are
acetyltransferase and phosphotransferase in this group [60].
Modified enzymes are responsible for the high extent of
gentamicin resistanceoinoenterococcio[61].
2. Ribosomal target Modifications
This approach is crucial in Streptomycin resistance, the
target of streptomycin is not connected to the ribosomal 30S
subunit due to mutations in the ribosomal 30S, in
enterococci, this kind of resistance to streptomycin is
essential [62].
C. The resistance of Tetracyclines
1. Prevention of the absorption of drugs into cells and
active pump systems
Reduction of membrane permeability resulting from
spontaneous chromosome mutations in bacteria as a result
of resistance development to prevent drug uptake [63]. The
organisms also can develop Tetracyclines resistance
depending on active pump systems [64].
2. Protection of Ribosome
The second significant mechanism which leads to
tetracycline resistance [65]. With tetM, tetO, tetQ, tetS genes
inhibit drug activity by modifying a cytoplasmic ribosome
that binds to the tetracycline [66]. These genes have been
found in many genera like Campylobacter, Mycoplasma,
Ureaplasma, and Bacteroides, for example. They are plasmid
and chromosome origin [67].
D. The resistance of Macrolide, lincosamide,
streptogramins (MLS)groups
Gram-negative bacteria are naturally resistant to MLS
group antibiotics
1. Ribosomal Target Modification
This mechanism is most common in Gram-Positive
bacteria, in the 50S ribosomal subunit, this is connected to
the drug with the 23S of the ribosome in rRNA-specific
methylation of an adenine molecule has a structural change
and reduces the drug's binding to ribosomal RNA. The
resistance is of a structural or inducible type [68,69].
2. Inactivation of drug by Enzymatic activity
The bacterial cells having enzymes that play a critical role in
resistance like Erythromycin and other Macrolides
resistance [70].
E. The resistance of Chloramphenicol
The inactivation of the chloramphenicol acetyltransferase
(CAT) by enzymes that acetylate the chloramphenicol
antibiotic leads to resistance in bacteria produced by this
enzyme [71]. Reduced drug uptake in certain bacteria
especially gram-negative can also be responsible for
chloramphenicol resistance [72].
F. The resistance of Quinolones
There are different mechanisms for quinolone resistance
that including
1. Mutation modification of the target topoisomerase
Modifications in the target enzymes topoisomerases
caused mainly by mutations that reduce the affinity of
quinolones without compromising the enzyme function are
the most common mechanism of acquired quinolone
resistance and have already been reported in several
bacterial species [73,74]. resistance-related mutations are
clustered in discrete regions of the enzyme subunits, called
regions determining quinolone resistance (QRDRs) [75].
2. A decreased intake of drugs by reduced permeability or
active efflux
Increased resistance to quinolones in gram-negative bacteria
due to variations in their outer membrane proteins so that
they reduce the intake of drugs [76].
3. The target protection of topoisomerase with specific
proteins
Target protection is provided by a family of small
pentapeptide-repeat proteins, called Qnr proteins, which
bind to the targets for topoisomerase and protect them from
quinolone interaction [77]. A similar mechanism has
developed in bacteria to protect topoisomerases from
microcin, which are pentapeptide-repeat family proteins
that are produced as a mechanism of biological competition
by certain bacteria and can kill susceptible bacteria by
inhibiting their topoisomerases [78].
4. Inactivation of the drug
The most recently identified mechanism of resistance to
quinolones was inactivation by drug modification [79].
Acetylation is performed by a plasmid-encoded AAC
enzyme variant which, has the ability to acetylate some
quinolone molecules in addition to aminoglycosides and
have unsubstituted secondary amines such as ciprofloxacin
and norfloxacin [80].

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820 Systematic Review Pharmacy Vol 11, Issue 6, 2020
G. Resistance of Rifampicin
The high-level resistance develops readily mainly due to
chromosomal mutation in most bacteria so developed of
stable changes that prevent binding in RNA polymerase
[81]. Rifampicin should only be used in association with
another antibacterial drug since the mutation risk is high.
Rifampicin resistance is not transferable, and other
antibacterials do not have cross-resistance [82,83].
H. Resistance of Sulfonamide and Trimethoprim
Sulfonamides are para-aminobenzoic acid analogs (PABA)
and the dihydropteroate synthesis (DHPS)enzyme and
trimethoprim dihydrofolate reductase (DHFR) metabolic
pathways inhibiting tetrahydrofolic acid synthesis in
bacteria [84,85]. Chromosomal and plasmid-mediated
resistance to sulfonamides and trimethoprim [86].
Bacterialoexpressionoof the DHPSosulfonamides low-
affinity plasmid comprising this case is the most commonly
observed resistance to sulfonamide [87,88].
FUNDING SUPPORT
This research did not receive any specific grant from
funding agencies in the public, commercial, or not-for-
profit sectors.
CONFLICT OF INTEREST
None to declare.
ETHICAL CLEARANCE
All data was approved and carried out in accordance with
approved guidelines.
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