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Antibiotics and the Mechanisms of Resistance to Antibiotics

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Antibiotics and the Mechanisms of Resistance to Antibiotics Review Article Pharmacology ANTIBIOTICS AND THE MECHANISMS OF RESISTANCE TO ANTIBIOTICS SALİH CESUR* ALİ P. DEMİRÖZ* SUMMARY: Microorganisms can develop resistance to antibiotics used in the treatment with a variety of mechanisms. In this article, the general mechanisms of resistance to antibiotics and resistance mechanisms that are frequently encountered in antibiotic groups were summarized. Key words: Antibiotics, antibiotic resistance, mechanisms. Resistance is the ability of a bacteria against the It has no hereditary property. It develops as result of the antogonizing effect of an antibacterial agent upon repro- natural resistance, or the microorganisms not including the duction prevention or bactericidal. The development of structure of the target antibiotic, or antibiotics not reaching resistance to antibiotics in bacteria often develop as a to its target due to its characteristics. For example, Gram- result of unnecessary and inappropriate use of antibiotics. negative bacteria vancomycin does not pass in the outer Through the intense use of antibiotics, resistant membrane so Gram-negative bacteria is naturally resist- microorganisms have emerged over the years, and ant to vancomycin. Similarly, L-form shape of bacteria problems were started to be experienced for the treatr- which are wall-less forms of the bacteria, and the bacteria ment of these infections emerged with these resistant such as cell wall-less cell Mycoplasma and Ureaplasma microorganisms. Today, on the one hand trying to are naturally resistant to beta-lactam antibiotics that inhibit develop new drugs, on the other hand, there are difficul- the cell wall synthesis (1,4-6). ties in treatment as a result of development of resistance 2. Acquired resistance: As result of the changes in to these drugs rapidly. The development of resistance to the genetic characteristics of bacteria, an acquired antibiotics is a major public health problem in all over the resistance occurs due to its not being affected from the world (1-3). antibiotics it has been responsive before. This kind of The main four types of resistance to antibiotics resistance occurs due to mainly structures of chromo- develops; some or extrachromosomal (plasmid, transposon, etc.). 1. Natural (Intrensic) resistance a. Chromosomal resistance arise from mutations in 2. Acquired resistance developing in spontaneous bacterial chromosome 3. Cross-resistance (spontaneous). Such mutations may occur according to 4. Multi-drug resistance and pan-resistance some physical (ultraviolet, etc.) and chemical factors. 1. Natural (Intrensic, Structural) resistance: This kind This can be a result of structural changes in bacterial of resistance is caused by the structural characteristics of cells. The result may be reduced permeability of bacter- bacteria and it is not associated with the use of antibiotics. ial drug or changes of the target of the drug may be in *From Department of Infectious Diseases and Clinical Microbiology, the cell. Streptomycin, aminoglycosides, erythromycin, Ankara Training and Research Hospital, Ankara, Turkey. lincomycin can develop resistance against these types. 138 Medical Journal of Islamic World Academy of Sciences 21:4, 138-142, 2013 ANTIBIOTICS AND THE MECHANISMS OF RESISTANCE TO ANTIBIOTICS CESUR, DEMİRÖZ Spontaneous chromosomal mutations are 10-7-10-12. in the structure of the target etc. If the bacterial strains Therefore such resistance in the clinic are less and often resistant to three or more classes of antimicrobials, it is does not cause a problem (1,4). considered as multi-drug resistant. If the strains, resistant b. Extrachromosomal resistance, depends extra- to all but one or two antibiotic gruops, they are considered chromosomal genetic elements that can be transferred as extensively-drug-resistant, if the strains resistant to all in various ways like plasmids, transposons and integro. available antibiotic, they are classified as pan-drug-resist- Plasmids are extrachromosomal DNA fragments ant. For example, multidrug resistance (MDR) Acineto- that can replicate independently from chromosome. bacter species (spp.) can be defined as the isolate Plasmid genes are usually responsible for the genera- resistant to at least three classes of antimicrobial agents tion of enzymes which inactive antibiotics. Resistance (namely, all penicillins and cephalosporins (including genes and plasmids carrying the genetic material from a inhibitor combinations), fluroquinolones, and aminoglyco- bacterium in three ways those are transduction, transfor- sides). Extensive drug resistant (XDR) Acinetobacter mation, conjugation, and transposition mechanism. spp.’ shall be the Acinetobacter spp. isolate that is resist- Transduction by bacteriophage resistance genes, ant to the three classes of antimicrobials described above transformation via DNA binding protein called compe- (MDR) and shall also be resistant to carbapenems. Pan- tence factor, conjugation via sex pilus between two live drug resistant or pan-resistant (PDR) Acinetobacter spp. bacteria through transfer of resistance genes. Antibiotic shall be the XDR Acinetobacter spp. that is resistant to resistance genes on the chromosome or plasmid is inter- polymyxins (colistin) and tigecycline (6-8). connected with each other and located near the start of specific units of integration is called integrons. Integrons MECHANISMS OF RESISTANCE TO ANTIBIOTICS are in warm regions where recombination (re-edited) is a. The changes that occur in the receptor that con- very common (1,4,5). nected to the drug and the region of the connection ‘Con- 3. Cross resistance: Some microorganisms which nection of the antibiotics’ target areas are different. They are resistant to a certain drug, that acts with the same or can be various enzymes and ribosomes. Resistance similar mechanism and also resistant to other drugs. associated with alterations in the ribosomal target are the This condition is usually observed in antibiotics whose most frequently observed in macrolide antibiotics. Muta- structures are similar: such as resistance between eryth- tions in penicillin-binding proteins (beta-lactamase romycin, neomycin-kanamycin or resistance between enzymes) and Staphylococcus aureus, Streptococcus cephalosporins and penicillins. However, sometimes it pneumoniae, Neisseria meningitidis and Enterococcus can also be seen in a completely unrelated drug groups. faecium strains can develop resistance to penicillin . There is an example of cross-resistance between eryth- Changes in the structure of the target, beta-laktam, romycin-lincomycin. This may be chromosomal or extra- quinolones, glycopeptides, macrolides, tetracycline and chromosomal origin (4,5). rifampicin resistance is an important mechanism in the 4. Multi-drug resistance and pan-resistance: Multi- development (10-13). drug-resistant organisms are usually bacteria that have b. Enzymatic inactivation of antibiotics: Most of become resistant to the antibiotics used to treat them. Gram-positive and Gram-negative bacterias synthesize This means that a particular drug is no longer able to kill enzymes that degrade antibiotics. This enzymatic inacti- or control the bacteria. Inapropriate use of antibiotics for vation mechanism is one of the most important mecha- therapy resulted in the selection of pathogenic bacteria nisms of resistance. In this group, beta-lactamases, resistant to multiple drugs. Multidrug resistance in bacte- aminoglycosides, modifying enzymes (acetylase, fosfo- ria can be occured by one of two mechanisms. First, riaz adenilaz and enzymes) degrade beta-lactam antibi- these bacteria may accumulate multiple genes, each otics and continually increasing their number of which coding for resistance to a single drug. This type of resist- inactivates enzymes include chloramphenicol and eryth- ance occurs typically on resistance (R) plasmids. Second romycin (1,5,12). type of resistance, namely multidrug resistance may also c. Reduction of the inner and outer membrane per- occur by the increased expression of genes that code for meability: This resistance due to changes in the internal multidrug efflux pumps, enzymatic inactivation, changes and external membrane permeability, decrease in drug Medical Journal of Islamic World Academy of Sciences 21:4, 138-142, 2013 139 ANTIBIOTICS AND THE MECHANISMS OF RESISTANCE TO ANTIBIOTICS CESUR, DEMİRÖZ uptake into the cell or quickly ejected from the active Class B beta-lactamases (Group 3): Stenotropho- resistance of the pump systems. As a result of a change monas maltophilia, Bacteroides fragilis, Aeromonas and in membrane permeability decreased porin mutations in Legionella detectable species, enzymes which hydrolyze resistant strains can occur in proteins. For example; in carbapenems as well as penicillin and cephalosporins Pseudomonas aeruginosa strains a specific porin called (3,5,17). OprD can cause to mutation carbapenem resistance. Class C beta-lactamases: Mainly parts cephalos- Reduction in permeability of the outer membrane may porins (cephalosporins). Usually found on Gram-nega- play an important role in resistance to quinolones and tive bacteria and localized to chromosome (Group I, aminoglycosides (1,5,12,14). AmpC etc.). Often the feature of inducible. Produced in d. Flush out of the drug (Active Pump System): high levels in the presence of a beta-lactam antibiotics Resistance developing through the active pump systems and are not inhibited by clavulanic acid. They are also mostly common in tetracycline group of antibiotics. called Inducible
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