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Objective:To investigate the mechanism of polymyxin resistance related to lipopolysaccharide modification in carbapenem-resistant Klebsiella pneumoniae (CRKP). Methods:Plasmid-mediated drug resistance genes in seven CRKP strains were detected by conjugation assay and mcr gene detection. The expression of polymyxin resistance-related genes was measured using quantitative real-time PCR. The complete genomes of CRKP strains were sequenced. Silver staining and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) were performed to analyze the changes in lipopolysaccharide (LPS). Results:The seven CRKP strains were negative for mcr genes and the results of conjugation assay were also negative. Moreover, no mobile genetic elements related to drug resistance were detected. Compared with wild-type strain, all seven CRKP strains that were resistant to polymyxin showed increased expression of pmrA, pmrB and pmrC genes at the transcriptional level; six showed increased expression of phoP/ phoQ genes; three showed decreased expression of crrA/ crrB genes; four showed decreased expression of mgrB gene. The missense mutation sites in drug-resistant strains were mainly in KPHS_09430, KPHS_35900, KPHS_39520 and KPHS_52420. IS Kpn14 insertion sequence was detected in CRKP-6 strain. MALDI-TOF-MS reveals the modification of natural lipid A with L-Ara4N in CRKP LPS. Conclusions:LPS modification induced by chromosome-mediated mutation in the two-component regulatory system was the main molecular mechanism of polymyxin resistance in CRKP isolates in this study. Effects of the mutation in the two-component system on polymyxin resistance varied in different strains.
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Streptococcus pneumoniae(SP)is one of the common pathogens of respiratory tract infection in children, which can evolve into severe pneumonia and necrotizing pneumonia in case of severe infection.β-lactam antibiotics are the first-line treatment for SP.The resistance mechanism of SP to β-lactam antibiotics is mainly PBPs gene mutation, followed by mutations related to non-PBPs genes such as MurM, CpoA, TEM, CiaH/CiaR-TCSS and StkP-PhpP signal conjugations.Antibiotic selection pressure and vaccine-induced serotype substitution may influence SP resistance.Serotypes 19F and 19A have high resistance to β-lactam antibiotics, and promotion of PCV13 may be more beneficial than other SP vaccines in preventing SP infection in children.
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Platinum anti-tumor drugs are currently the most widely used first-line chemotherapeutic drugs in clinical practice, and their curative effects are remarkable. However, the problems of platinum drug resistance in non-small cell lung cancer, breast cancer, ovarian cancer and others seriously limit effectiveness and clinical application of platinum drugs. The occurrence of platinum drug resistance is caused by many factors. At present, the resistance mechanism of platinum drugs mainly includes the following aspects: decreasing the accumulation of platinum in cells, increasing the inactivation of platinum in cells, repairing DNA damage and tumor cell apoptosis inactivation. This article reviews the drug resistance mechanism and coping strategy of platinum anti-tumor drugs, providing ideas for the development of platinum anti-tumor drugs and references for overcoming clinical platinum drug resistance.
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The MET gene is an important tumor-driving gene for non-small cell lung cancer (NSCLC). Drugs targeting tumor with MET exon 14 skipping mutations bring new hope for patients. Although MET inhibitors such as tepotinib and savolitinib have shown good antitumor effects, resistance is inevitable. Studies on the hepatocyte growth factor (HGF)/mesenchymal- epithelial transition factor (MET) signaling pathway will not only help explore the mechanism underlying resistance to MET inhibitors, they may aid in the discovery of strategies for inhibiting and reversing drug resistance, thereby expanding the field of novel drug development. Preliminary studies have shown that the combination of HGF/MET inhibitors with other drugs may have great potential for clinical applications. This article reviews the characteristics of MET gene abnormalities, the mechanism of resistance against MET inhibitors, and the strategies for responding to resistance. Finally, the challenges posed by MET inhibitors is discussed and guidance on the direction of future development of MET inhibitors is proposed.
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Objective@#To investigate the molecular mechanism of colistin resistance in Klebsiella pneumoniae (K.pneumoniae).@*Methods@#Three clinical isolates of colistin-resistant K. pneumoniae (FK1149, FK1920 and FK1934) and three colistin-resistant mutants (FK660R, FK713R and FK729R) were investigated. Resistance genes of pmrAB, phoPQ, mgrB, crrAB, mcr-1 and mcr-2 were detected by PCR and then analyzed by sequencing. PROVEAN platform was used to predict changes in the biological functions of proteins related to drug resistance. Expression of pmrH, pmrC, mgrB and phoP genes was measured using quantitative real-time PCR. LPS silver staining and conjugation assay were performed to analyze the three clinical colistin-resistant isolates.@*Results@#Amino acid substitutions in PmrA (G53V), PmrB (T157P, R256G), MgrB (F44C) and CrrB (E189K) were detected. ISkpn14 and IS5-like insertion sequences were detected in FK713R and FK729R, respectively. FK1149, FK1920 and FK1934 were negative for mcr genes. Compared with the wild-type strain, expression of pmrH and pmrC genes at the transcriptional level was increased in all investigated isolates. Changes in the expression of phoP and mgrB genes were also observed. A partial deletion of LPS was identified in FK1149.@*Conclusion@#LPS modification induced by inactivation of PmrAB or MgrB is the main molecular mechanism of colistin resistance in K. pneumoniae isolates in this study. Mutations in PmrA (G53V), MgrB (F44C) and CrrB (E189K) that might be related to colistin resistance are detected for the first time in clinical isolates of K. pneumoniae.
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Antibiotics are critical weapons that were used for combating human pathogens. However, the heavy use of antibiotics leads to the increased and widely spread of antimicrobial resistance. The antimicrobial resistance is not only a medical problem, but also social and economic concerns, involving public health, environmental pollution, food safety, etc. This special issue reviewed and discussed the recent progress on antimicrobial resistance regarding the fields of clinical drug resistance and epidemiology, animal and environmental drug resistance, drug resistance mechanisms, antimicrobial drug development and drug resistance prevention and control, hoping to give a comprehensive view on basic antimicrobial resistance questions, future research directions and prevention and control strategies.
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Mycoplasma pneumoniae (M. pneumoniae) is one of the predominant pathogenic bacte-ria causing community acquired pneumonia. An epidemic of M. pneumoniae infection occurs every three to seven years worldwide. It can cause a variety of clinical symptoms. Since 2000, macrolide-resistant M. pneu-moniae strains have become increasingly common in many countries around the world and the drug resistance rate has reached as high as 100% in some area, which has posed a great threat to human health. This paper will review the status and mechanism of drug resistance in M. pneumoniae.
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Cytarabine is an anti-metabolic drug with cytotoxicity, which plays an important role in the treatment of acute leukemia. Cytarabine mainly acts on S proliferation phase of tumor cells. Normally, cytosine integrates with deoxyribose to form deoxycytidine, which is one of the components of DNA. Cytarabine is a deoxycytidine analogue, which can replace the former to form DNA. Therefore, it inhibits the synthesis of cellular DNA, interferes with the proliferation of tumor cells and achieves the therapeutic purpose, due to the different structure. Different genetic backgrounds and different efficiencies of drug absorption, metabolism and elimination may result in changes in the effectiveness of the drug regimen containing cytarabine, which may affect the survival of patients with acute leukemia. The research progress of drug resistance mechanism of cytarabine in acute leukemia is reviewed and summarized in this paper.
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Objective To explore the molecular mechanisms of carbapenem-resistant Klebsiella pneumoniae.Methods Carba NP confirmatory test were used to detect carbapenemases.Carbapenemase genes,ESBL genes and plasmid-mediated AmpC genes were amplified by polymerase chain reaction (PCR).The genetic correlation analysis was carried out by using multiple sequence type (MLST).Results 42 out of the 50 carbapenem-resistant Klebsiella pneumoniae strains were KPC-2-positive strains,1 strain was positive for NDM-1,the other 7 strains were not detected for any carbapenemase genes.The percentages of KPC-2-positive Klebsiella pneumoniae with the bla CTX-M,bla SHV,bla TEM,bla DHA were 21.5 ％,42.9 ％,69.1％ and 4.8％ respectively.The results of MLST showed that 37 out of 42 KPC-2 positive strains were ST11.Conclusion The production of KPC-2 is the main mechanism of Klebsiella pneumoniae resistance to carbapenem and there is an outbreak of ST11 KPC-2 Klebsiella pneumoniae in this hospital.
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Community associated methicillin-resistant Staphylococcus aureus is a human pathogen.It can cause a series of infections cause morbidity and mortality,including bacteremia,pneumonia and soft tissue infections.USA300 clone is highly toxic and contagious.Its prevalence in the United States continues to rise,and has begun to spread to the rest of the world.This article briefly reviews the recent research on relevant aspects of molecular epidemiological characteristics,grug resistance mechanisms and treatment of USA300 clone.
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Pyrazinamide (PZA) is an important anti-tuberculosis drug especially for treating multidrug-resistant tuberculo sis (MDR-TB).In recent years,the incidence of Mycobacterium tuberculosis' resistance to pyrazinamide has increased.At present,the mechanism of drug resistance has not been clearly elucidated.In this review,the association between gene mutation and pyrazinamide resistance in Mycobacterium tuberculosis will be summarized.
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Objective To reversing methicillin-resistant Staphylococcus(MRS) to methicillin-susceptible Staphylococcus(MSS) by changing nutritional conditions and continuous transfer of culture .Methods MRS trains separating from clinical specimens were cultured in different conditions ,continuous cultural transfer ,and drug sensitive test were proceeded periodically to observe the phe-notypic and chemical reaction change of MRS .The mecA gene were detected of the original and mutant strains by polymerase chain reaction(PCR) ,then the gene sequenced and compared .Results 53 MRS strains were studied .6 strains were phenotype successful-ly converted to MSS in different cultural conditions ,among them mecA gene was undetected in 2 strains ,and down expressed in 4 strains .Conclusion The MRS strains separated from clinical specimens may revert to MSS by culture under different nutritional conditions .The mecA gene of MRS may be lost or lower expressed and the MRS and mutant strains may be different in genomics .
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Objective To study antimicrobial resistance of clinically isolated Escherichia coli (E.coli),the preva-lence of integrons in E.coli,and relation of integron with antimicrobial resistance of E.coli.Methods E.coli isola-ted from three hospitals of Guangdong Province from 2010 to 2012 were collected,and antimicrobial susceptibility testing was performed by Kirby-Bauer method;integrons were detected by polymerase chain reaction (PCR),and gene cassette was analyzed by sequencing.Results A total of 156 E.coli isolates were collected,antimicrobial sus-ceptibility testing showed that resistance rate of E.coli to most penicillins,cephalosporins,fluoroquinolones,amin-oglycosides and sulfonamides were over 50%;the resistance rate to antimicrobials 0.05),but compared with sensitive E.coli (9.09%,2/22),the difference was statisti-cally different (P<0.01 ).There were nine types of integron-drug resistant gene cassettes in the variable regions, most of which contained aadA and dfrA.Conclusion Antimicrobial resistance of E.coli is serious;high incidence of class I integrons are widely found in E.coli,and is closely related with drug resistance of E.coli,class I integrons mainly mediated aminoglycosides,sulfonamides and beta-lactams resistance.
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Pseudomonas aeruginosa is the first gram-negative bacillus pathogen of hospital-acquired infection.With the widely application of the antibiotics,pseudomonas aeruginosa resistant rate is rising,which causes refractory infection.Controlling and preventing the bacterial infection are the most important work in ICU.In this paper,we reviewed the pseudomonas aeruginosa resistant mechanism and the change of resistance,providing a reference for clinical diagnosis and treatment in PICU.
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OBJECTIVE To investigate the resistance of Acinetobacter baumannii(ABA),and the mechanism of imipenem resistance in A.baumannii.METHODS All specimens were identified by VITEK-60 and the drug resistance was detected by Kirby-Bauer test.Three dimensional test was used to detect ESBLs and AmpC.PCR and DNA sequencing were performed to determine VIM,IMP,OXA-23 and OXA-24 ?-lactamases.Outer membrane protein was analyzed by SDS-PAGE,Reserpine synergistic inhibition test was used to study the active efflux mechanism.RESULTS Totally 120 strains were isolated from sputum(76.9%),and 16 strains from secretion(10.3%).ICU was the main infected department(51 strains,32.7%).The resistance to sulperazone was the lowest(20.5%),and to imipenem accounted for 38.5%,Of the 20 imipenem resistant strains,10 strains were ESBLs positive(50%),and 20 strains were AmpC positive(100%).VIM,IMP and OXA-24 ?-lactamases were not detected out,19 strains(95%) produced OXA-23.Compared to the imipenem-sensitive strains,the resistant strains lacked the outer membrane protein of 22?103,29?103 and 33?103.The MICs of A.baumannii to imipenem were not decreased by reserpine which demonstrated that excretive mechanism was negative.CONCLUSIONS ICU is the main infected department for ABA.The resistance rate is increasing for longer-term usage of carbopenem;OXA-23 production is the important resistance mechanism in ABA,AmpC production and outer membrane protein lacking show close relation to the drug-resistance in A.baumannii.
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OBJECTIVE To sudy drug resistance related gene of carbopenem resistant Pseudomonas aeruginosa and type 1 integrating enzyme gene.METHODS With PCR method to detect and analyze carbopenem resistant P.aeruginosa pertinent metal ?-lactamase IMP,VIM,SPM,GIM genes and cell membrane protein oprD2 gene and six main drug resistance genes of type Ⅰ integrating enzyme gene and five others.RESULTS Fifty one strains of imipenem and meropenem resistant P.aeruginosa SPM,GIM metal enzyme genes were detected to be negative,16 strains of IMP and 5 strains of VIM type metal enzyme were all positive,14 strains of carbopenem resistant P.aeruginosa oprD2 gene were positive,other 37 strains of P.aeruginosa oprD2 gene were negative,7 strains produced metal enzyme and cell membrane protein oprD2 gene were deleted at the same time,49 strains with type Ⅰ integrating enzyme gene intⅠ1 were positive.CONCLUSIONS It is indicated the gene deletion of P.aeruginosa outer membrane protein OprD2 is important mechanism of carbopenem resistant P.aeruginosa,the second is metal enzyme,type Ⅰ integrating enzyme exists largely in P.aeruginosa.This hints the monitoring that drug resistance gene spreads and propagates in bacterium strain must be reinforced.