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| Reference |
| Molecular biology mechanism and control measures of the bacterial drug resistance |
Key words: bacteria; resistance mechanism; control measures
Since the inception of penicillin, antibacterial drugs in the clinical application of the results obtained attract people's attention. With the wide application of antibacterial drugs, bacterial resistance also. In recent years, by the use of antibacterial drugs caused by antibiotic-resistant bacterial resistance is also increasing, more and more widely, more and more high degree, multiple drug-resistant strains appear constantly, and drug resistance through the food chain transfer to the crowd, which greatly endanger human oneself safety. The mechanism of bacterial drug resistance and resistance to control measures are elaborated.
1 molecular biology mechanism of bacterial resistance to antibiotics
1.1 bacterial damage drug structure of inactivated enzymes
This class of drug resistant bacteria can often produce one or more of the inactivated enzyme or enzyme inactivation to hydrolysis or modified into bacterial cells within the drug, so that the loss of biological activity, which is caused by a bacterial drug resistance is the most important mechanism. The main enzyme with beta lactamase, Ms aminoglycoside acetyltransferase inactivating enzymes, enzyme inactivation, erythromycin and other.
MS 1.1.1 beta lactamase ( beta around lactamase ) this bacteria is on beta lactam antibiotics resistance around the main reason. The enzyme can be mediated chromosomal, also can be mediated by plasmid. The former goods by changing the beta lactam antibiotics of the target is penicillin binding protein ( PBP ); the latter by hydrolysis and non hydrolytic way to beta lactam ring, around the amide bond breakage and the antibacterial activity of antibiotics to lose. Bush beta lactamase MS will be divided into 4 types, type I is not being clavulanic acid inhibition of cephalosporins enzyme ( AmpC enzyme ), type II can be inhibited by the inhibitors beta lactam enzyme action, type III is not to be inhibitors ( ethylenediaminetetraacetic acid and formic acid except) inhibited by the metal beta right lactam enzyme, type IV is not being clavulanic acid inhibition of penicillin. In part I, II type is particularly important, type I enzymes for chromosome and plasmid mediated by the generation of AmpC beta lactamase MS, plasmid mediated AmpC enzyme, the AmpC has no regulatory genes, sustained high expression, according to the chromosomal origin is divided into 5 families: cyclophos phamide Citrobacter origin of group LAT; II. The unknown origin of group FOX; the Enterobacter cloacae origin of group Entb; the origins of the group Morg Mohs Morgan bacterium hafnia alvei; the origin of the Haf family. Chromosome mediated AmpC enzymes are divided into 4 types: 1. Ia inducible, found in Enterobacter cloacae; II Ib continuous type, found in Escherichia coli; 3. Ic inducible, found in Proteus vulgaris; the Id inducible, found in Pseudomonas aeruginosa. Type II enzyme is produced by plasmid mediated extended-spectrum beta lactamase ( MS extended spectrum beta around lactamases, ESBLs ), to November 20, 2007 countrywide has discovered that the ESBLs has more than 500 [1 ], according to the coding gene homology is divided into TEM, SHV, CTX around M, OXA and the other 5 categories.
1.1.2 aminoglycoside modifying enzyme of bacteria aminoglycoside antibiotic resistance is the most important reason is to produce drug of this class of covalent modification of enzyme. The enzyme is divided into 3 categories, namely acetyl transferase ( AAC ), phosphoric acid transferase ( APH ) and adenylyl transferase ( AAD ). They can be aminoglycoside antibiotic free amino acetylation, phosphorylation or nucleoside free hydroxyl groups, so that the drug is not easy to enter the bacterial body, also not easy and bacteria within the target ( ribosomal subunits with 30 S ), thus losing the inhibition of protein synthesis ability. Has been found in genotype has exceeded 30, which G coli AAC (3 ) AAC ( 3), the right of action II, AAC (6 ) AAC ( 6 ms I," Ms II ), ant (3" ) because I, ant ( 2 ms ) gene is a common G; neoformans in AAC (6 ) / APH ( 2 ), APH ( 3 ) ant ( 6), the right of action for common gene. Robiscek A [2 ] confirmed the plasmid mediated aminoglycoside acetyltransferase AAC (6 ) Ib Cr MS MS to quinoline re ketones drug activity, first discovered by a gene coding for the enzyme to two kinds of structures of different antibiotic substrates simultaneously active phenomenon.
1.1.3 chloramphenicol acetyltransferase this enzyme is an intracellular enzyme, the cat gene family encoding, its expression product modification of chloramphenicol inactivates it.
1.1.4 erythromycin enzyme inactivation of this enzyme is an enzyme plasmid mediated by constitution. Includes: 1 erythromycin esterase: Enterobacter capable of carrying ereA gene and ereB gene expression in the erythromycin erythromycin esterase inactivation of ester solution; erythromycin phosphotransferase: by mphA, mphB and mphC encoding genes, their expression products can make two erythromycin DNA methylamine hexose C 2 ' position of phosphorylation or glycosylation and loss live [3]; the Virginia DX acyltransferase: this enzyme in Staphylococcus aureus by vatA, vatB, vatC coding, in enterococci in the vatD, vatE coding. The expression product of activity modification effect on Virginia.
1.2 target change
Drug target change will lose its site of action, so that the drug out of action. Research shows, macrolide-resistant bacteria through ERM genes encoding ribosomal methylase, located in the ribosome subunit 50 S 23 S rRNA adenine methylation, leading to antimicrobial drugs cannot be combined with binding site [4 ]. So far, more than 20 had detectable ERM gene, common ermA, ermC, ermAM [5 ]; 16 bacterial S rRNA gene mutation, aminoglycoside antibiotics will be lost; quinolones major role in bacterial DNA gyrase and topoisomerase and antibacterial effect, when the encoding DNA gyrase gyrA ( mutation site focused on the near Ser83), gyrB gene, encoding topoisomerase parC, parE gene mutation, through its expression product of changing the conformation of lead resistance, the researchers put forward mutation inhibitory concentration ( mutants prevention concentration, MPC ) concept [6 7 ]. Streptococcus pneumoniae through its penicillin binding protein gene ( pbp1A, pbp2B ) mutations, on the penicillin resistance [8 ].
1.3 bacterial biofilm formation
Bacterial biofilm ( bacterial biofilm, BBF ) refers to the bacterial adhesion to solid or organic cavity surface, forming a microcolony, and secretion of extracellular polysaccharide-protein complexes which wrapped itself and the formation of membrane. Bacterial biofilm formation, often resistance to antimicrobial drugs, the main reasons are as follows: the bacterial biofilm in the extracellular polysaccharide barrier, can reduce antimicrobial drug penetration of antimicrobial agents; adsorption of enzyme inactivation of antibacterial drugs, promote hydrolysis; the bacteria in the biofilm under low metabolism, on the antibacterial reduced drug susceptibility; the biofilm prevented the organism against bacterial immunity, immune escape, weakened immunity and antibacterial synergistic germicidal effects [9 ]; the biofilm formation in favor of antibiotic efflux pump synthesis [10 ]. Can form biofilms of clinical common pathogenic bacteria were Pseudomonas aeruginosa, Staphylococcus aureus and Escherichia coli.
1.4 obstacles to bacteria within the penetration of antimicrobial drug
Bacterial cell wall barrier or changes in membrane permeability, so that antibiotics cannot enter the cells reach the target and play the antibacterial efficacy, this bacteria is itself a kind of defense mechanism. This class of bacteria found in Gram-negative bacteria, and cell wall structure. Bacterial mutation lost some specific pore proteins can lead to bacterial resistance, such as Escherichia coli due to outer membrane protein F ( OmpF ) deficiency, the increase of OmpC ( sometimes drop) that certain drugs lose their antimicrobial activity [11], caused by deletions of OmpF mechanism is mainly due to the bacterial chromosome region Mar gene mutation induced by. Escherichia coli Mar gene located on the bacterial chromosome 34 points a, Mar sites in maro as the center, contains 2 operons, where maro is the mar of the control region, which contains a transcription promoter and MarA, MarR protein binding sites.
1.5 active efflux system ( efflux pumps )
Bacterial cell membranes are a class of proteins, in energy support, drug selective or nonselective discharged from the bacterial cells, this process is called active efflux system hyperfunction, so that reach the target drug concentration decreased and the lead resistance [12 ].
Bacterial multiple antibiotic resistance associated with the active efflux pump system is mainly attributable to the following 5 family / class [13]: 1. ATP binding cassette transporter class I binding cassemembrane affinity [ATP filtration ( ABC ) transporters, ABC ]; the main Yi Huachao family ( major facilitator superfamily, MFS ); the drugs and metabolites transporter family [drug / metabolite transporter ( DMT ) superfamily], such efflux transporters in bacterial drug resistance associated with a" multiple drug resistance ( small multi I drug resistance, SMR )" efflux pumps; the multiple drugs and poisons efflux family ( multidrug and toxic compound extrusion, MATE );. MS MS student section split tolerance family ( resistance nodu1ation division MS MS [RND] family, RND ). The above types of transporters in class ABC to ATP hydrolysis energy driving efflux pumps, the rest of the are in the proton motive force for energy, and the formation of the proton and the reversal of drug transporting body.
In recent years, has been studied by a variety of bacteria of active efflux systems, such as Escherichia coli RND multiple drug efflux pump system MS MS AcrA AcrB TolC [14], and in the clinical multiresistant Escherichia coli study found that the existence of tetracycline and sodium salicylate active efflux system [15 ], Pseudomonas aeruginosa bacterium of active efflux system MexAB OprM MexCD OprJ, Ms MS MS, MexEF OprN [16 ], Bacillus subtilis cell membrane Bmr active efflux system [17 ]. Active efflux of drugs has been thought to be the result of bacteria to various antibiotics resistance is one of the important reasons. In addition, integrons belongs to mobile genetic elements, capable of carrying recombinant gene cassette is inserted into the transposons or conjugative plasmids, in different bacterial movement and the spread of drug resistance, at the same time an integron can capture more gene cassettes, causing the bacteria to produce multiple resistance [18 ].
2 main measures for control of bacterial drug resistance
2.1 general measures
To make an accurate diagnosis of 2.1.1 disease, the rational use of antibiotics. This requires that basic level veterinary staff improve diagnostic skills and strengthen the relevant medical knowledge, an antidote against the disease. Master the medication knowledge, to narrow spectrum spectrum, first after first-line second-line drug delivery sequence and combined with medication, should strictly control the abuse of antibacterials, on bacterial infectious diseases do not blindly use of antibacterial drugs. In the use of antibacterial drugs in the treatment of diseases, conditions for drug sensitivity test, high sensitivity, low scientific selection of drugs.
2.1.2 in breeding production, as far as possible without antimicrobial drugs to prevent disease, should improve the immunity of animal, through its own to resist the disease infection.
2.1.3 strengthen animal drug management, crack down on fake and shoddy products. Veterinary drug production enterprises should strictly enforce the GMP standard, veterinary drug enterprises should achieve GSP certification.
2.1.4 close monitoring of antimicrobial drug resistance, to provide resistance prevalence data. Upon discovery of resistance, should reduce the use of medication, or even stop using.
2.2 of the drug itself improvement
2.2.1 uses traditional Chinese medicine means to remove R plasmid, control of bacterial drug resistance traditional Chinese medicine with little side effect, not easy to produce drug resistance characteristics, Chinese medicine from the selected for in vivo R plasmid elimination agent, for the control of bacterial resistance spread and the development of Chinese traditional medicine using all has the extremely vital significance. Traditional Chinese medicine in vitro performance for single resistance loss, the in vivo role was for multiple resistance loss [19 ]. The single Chinese herb plasmid elimination rate to be lower than the compound, may be the use of performance similar to the drug compound composition has synergistic effect, enhances drug efficacy [20 ]. Rale long [21 ] on Escherichia coli ciprofloxacin resistance eliminating research, found that its extract on Escherichia coli ciprofloxacin resistance eliminating.
2.2.2 could not find the use of antibiotics to treat bacterial infection of new strategy of damage resistance genes, the sensitivity to antibiotics of bacteria recovered; the development of antimicrobial peptides, because of its unique biological activity and is different from the traditional antibiotic special action mechanism, has aroused great interest in the study; the development of more specific bacterial vaccine.
2.2.3 research and development of new antimicrobial drugs according to the occurrence of bacterial resistance mechanisms and antibacterial drugs and structural relationships, looking for and the development of antimicrobial activity, especially on drug-resistant bacteria have activity of new antibacterial drugs. Such as the use of new technologies such as nanotechnology, improve the targeting of drugs and drug release properties, in order to strengthen the new antibiotics and its compound preparation.
2.2.4 development using phage preparation of different kinds of phage lytic mechanisms exist differences, with large genome of bacteriophage Hollin proteins on MS Endolysin system [22 ], and the small genome of the bacteriophage only encodes a protein dissolved, can play a similar to penicillin kind of role, through inhibiting cell wall synthesis and sterilization.
2.2.5 development of bacterial antagonists of inactivating enzyme inhibitors. There have been 3 kinds of beta lactam enzyme inhibitor MS, including clavulanic acid, Shu TAZ and three Zuo Batan, all of them with beta lactam ring around, can be around with beta lactamase competitive binding, protection of penicillins and cephalosporins drugs cannot be inactivated, but its antimicrobial activity was minimal, often with other antibacterial drugs; the membrane permeability agent. Some antibiotics such as polymyxin, aminoglycosides and macrolide through disruption of the bacterial cell membrane integrity, increasing the permeability of the membrane and reach the antibacterial function; the efflux pump inhibitors. Marquez B [23 ] from the Jatropha plant roots of extracted compounds, which belongs to the pyridine two carboxylate esters, against Staphylococcus aureus in NorA pump has better inhibition effect, Maria R F [24 ] from the 25 Brazil traditional plant extracted 9 compounds, the resistance of gold staphylococcus aureus has higher activity; quinolone efflux pump inhibitor MC 207110, can obviously inhibit Pseudomonas aeruginosa Mex efflux pump system and Escherichia coli AcrAB efflux pump system; 13 MS CPTC is a tetracycline (TC ) derivatives, can be competitive with the bacterial type B tetracycline efflux pump [ Tet ( B ) protein] binding, blockade of Tet (B) and T |
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