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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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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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Salmonella are important food-borne infectious bacteria causing gastroenteritis, enteric fever, bloodstream infection and focal extraintestinal infection and other salmonellosis.It is a major global public health problem.Antibiotics play an important role in the prevention and treatment of salmonellosis.With the emergence of resistance to traditional first-line drugs for the treatment of salmonellosis, azithromycin has become one of the commonly used antibiotics.However, studies have reported azithromycin resistant Salmonella strains, and azithromycin resistance in Salmonella is becoming more common and increasing year by year.Enhanced activity of active efflux pump, destruction of lactone ring structure, methylation of ribosome, carrying ICE_erm42 gene may be related mechanisms of drug resistance.The discovery, monitoring and in-depth study of azithromycin resistance in Salmonella play an important role in the rational use of antibiotics and delaying the trend of resistance.This article reviews the research progress on the epidemiology and related mechanisms of azithromycin resistance in Salmonella.
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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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Stenotrophomonas maltophilia is a gram-negative bacillus which widely exists in natural and hospital environment, and it is also one of the common opportunistic pathogens in clinical settings. The virulence and pathogenicity of Stenotrophomonas maltophilia are weak, however, due to resistance to a variety of antibacterial drugs, it can cause bloodstream infections or pneumonia in immunocompromised or critically ill patients, leading to poor prognosis. Moreover, the inherent drug resistance and increasing acquired drug resistance may make the treatment of the first line antibiotics, like trimethoprim-sulfamethoxazole or quinolone ineffective. Therefore, it is important to understand the drug resistance mechanism and the main countermeasures for it. In this article, the research progress on drug resistance mechanism and treatment for Stenotrophomonas maltophilia are reviewed.
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With th e massive use of antibiotics ，Klebsiella pneumoniae has shown a trend of multiple drug resistance ， especially carbapenem-resistant K. pneumoniae ，which means that fewer and fewer antibiotics can be used to treat K. pneumoniae infection. Polymyxin has become the last line of defense for the treatment of carbapenem-resistant K. pneumoniae infection due to its unique antibacterial mechanism. However ，with the increase of its use ，the reports of drug-resistant K. pneumoniae strains at home and abroad are also on the rise ，seriously endangering the lives of patients . The author summarizes the resistance mechanism of K. pneumoniae to polymyxin ，and find that the resistance mechanism of K. pneumoniae to polymyxin mainly includes the structural modification of lipopolysaccharide in bacterial outer membrane ，the overexpression of capsular polysaccharide and the overexpression of multidrug efflux pump ，which can provide a basis for the rational use of the drug and the prevention and treatment of drug-resistant K. pneumoniae .
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The cultivation and production of cucumber are seriously affected by downy mildew caused by Pseudoperonospora cubensis. Downy mildew damages leaves, stems and inflorescences, and then reduces the yield and quality of cucumber. This review summarized the research advances in cucumber downy mildew, including pathogen detection and defense pathways, regulatory factors, mining of pathogens-resistant candidate genes, proteomic and genomic analysis, and development of QTL remarks. This review may facilitate clarifying the resistance mechanisms of cucumber to downy mildew.
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Cucumis sativus/genetics , Oomycetes/genetics , Peronospora , Plant Diseases/genetics , ProteomicsABSTRACT
Extracellular vesicles (EV) are lipid bilayer vesicles with a diameter of 30-1000 nm secreted by cells or microorganisms, which are abundant in proteins, nucleic acids, lipids and other biological information molecules. Therefore, EV can be used as a carrier, transferring materials between cells. At present, in infectious diseases, EV derived from pathogenic microorganisms could be considered as a double-edged sword, which means it can not only play a negative role in the host′s infection immunity, bacteria′s pathogenicity and antibiotic resistance transmission, but also manifest the advantages in clinical diagnosis and treatment.
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Patients with oncogenic driver alterations of non-small cell lung cancer (NSCLC) can benefit from targeted therapy, but acquired resistance is inevitable ultimately. Epigenetic modifications, including DNA methylation, histone modifications, non-coding RNA-mediated regulate and chromatin remodeling, are important mechanisms of acquired resistance in targeted therapy of NSCLC. In recent years, studies have found that epigenetic modifications can effectively reverse drug resistance. Targeted therapy combined with epigenetic modifications may become a promising therapeutic strategy. Here, we review the progress of epigenetic mechanism in acquired resistance of targeted therapy in NSCLC, hoping to provide ideas for screening dominant population and overcoming resistance. .
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Humans , Carcinoma, Non-Small-Cell Lung/genetics , DNA Methylation , Epigenesis, Genetic , Lung Neoplasms/geneticsABSTRACT
Inhibition of immune checkpoints is at the forefront of immunotherapy for lung cancer. However, a high percentage of lung cancer patients do not respond to these immunotherpy or their responses are transient, indicating the existence of immune resistance. Emerging evidence suggested that the interactions between cancer cells and immune system were continuous and dynamic. Here, we review how a range of cancer-cell-autonomous characteristics, tumor-microenvironment factors, and host-related influences account for heterogenous responses. Furthermore, with the identification of new targets of immunotherapy and development of immune-based combination therapy, we elucidate the methods might useful to overcome resistance.
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PD-1/PD-L1 plays a pivotal role in the inhibition of T lymphocytes and tumor immune escape. Immunological checkpoint inhibitors of PD-1/PD-L1 can restore inactivated T cells and enhance the ability of killing tumor cell. At present, PD-1/PD-L1 inhibitors have been used in a variety of tumor types. Although some patients prove significant effects, there are still some patients with primary or acquired resistance to PD-1/PD-L1 inhibitors. The mechanism of resistance is related to the loss of the first signal or costimulatory signal, the expression of PD-1/PD-L1,the expression of other immune checkpoints on the surface of T cells, the immunosuppressive tumor microenvironment and systemic immunity. And we will find ways to prolong the survival time of patients through the combination therapy. This article mainly reviews the resistance mechanism and combination therapy of PD-1/PD-L1.
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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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BACKGROUND: As a potential candidate that can be extracted from natural sources and used to fight antibiotic-resistant bacteria, antimicrobial peptides have attracted extensive attention of scientists. Familiarity with the antimicrobial mechanism of antimicrobial peptides is conducive to the clinical application of antimicrobial peptides. OBJECTIVE: To review the advance in research of antimicrobial mechanism of antimicrobial peptides. METHODS: The first author conducted a computer-based retrieval of PubMed, Springeriink, Web of Science. ScienceDirect databases for articles regarding the antimicrobial mechanism and research advance published from January 2013 to March 2019. RESULTS AND CONCLUSION: Antimicrobial peptides are a class of special molecules with broad-spectrum antimicrobial activity. In some organisms, antimicrobial peptides arc considered lo bo an important part of innate immune system. The antimicrobial mechanism of antimicrobial peptides can be divided into two main modes: direct killing and immune regulation, and direct killing mechanism can be further divided into membrane targeting and non-membrane targeting. At the same time, based on the extensive application of antimicrobial peptides, it is expected that many resistance strategies have been developed in microbial environments such as staphylococcus, oral bacteria (including streptococcus) and intestinal bacteria (including salmonella). These resistance strategies mainly include passive resistance and induction or adaptive resistance mechanisms. In the future research and application, cationic peptide is an effective choice to solve the increasing multidrug resistance. In addition to the obligation to design new methods to combat the resistance of antimicrobial peptides in bacteria, general preventive measures against the resistance of conventional antibiotics should also be paid attention to.
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Melanoma is a malignant tumor of melanocyte origin, and BRAF mutations occur in about 50% of melanoma patients clinically. BRAF inhibitors can target mutated BRAF sites, thus rapidly inhibiting the proliferation and promoting apoptosis of tumor cells. However, the subsequent rapid occurrence of drug resistance events seriously restricted the continuous use of such drugs, so it is of great importance to explore the mechanism of BRAF inhibitors resistance. This paper introduces the research progress of BRAF inhibitor resistance in melanoma in recent years, in order to provide some references for the follow-up research and clinical application.
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Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis (M. tb) and mainly spread by airborne transmission, remains a global health problem. After the wide clinical utilization of antibiotics in treatment of TB, the drug resistance has become a major threat to global TB control and this threat has been heightened by the emergence and propagation of multi-drug resistant tuberculosis (MDR-TB), extensively drug-resistant tuberculosis (XDR-TB) and totally drug-resistant tuberculosis (TDR-TB). The research in the mode-of-action mechanisms of anti-TB drugs and the drug resistance mechanisms of M. tb will facilitate the novel anti-TB drugs development, the optimization of current anti-TB drugs and the development of new drug resistance diagnosis technologies. This review provides a comprehensive overview of mode-of-action mechanisms of new anti-TB drugs and mechanisms of resistance to these drugs in M. tb, with particular attention to the role of newly-identified mycobacterial outer-membrane channel proteins (PE/PPE proteins) in TB drug resistance.
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Background & objectives: Azithromycin has been in use as an alternate treatment option for enteric fever even when the guidelines on the susceptibility testing were not available. There is lack of data on susceptibility and mechanisms of resistance of azithromycin in Salmonella Typhi and S. Paratyphi A. The aim of the present study was to determine the azithromycin susceptibility and resistance mechanisms in typhoidal salmonellae isolates archived in a tertiary care centre in north India for a period of 25 years. Methods: Azithromycin susceptibility was determined in 602 isolates of S. Typhi (469) and S. Paratyphi A (133) available as archived collection isolated during 1993 to 2016, by disc diffusion and E-test method.PCR was done for ereA, ermA, ermB, ermC, mefA, mphA and msrA genes from plasmid and genomic DNA and sequencing was done to detect mutations in acrR, rplD and rplV genes. Results: Azithromycin susceptibility was seen in 437/469 [93.2%; 95% confidence interval (CI), 90.5 to 95.1%] isolates of S. Typhi. Amongst 133 isolates of S. Paratyphi A studied, minimum inhibitory concentration (MIC) of ?16 mg/l was found in 102 (76.7%; 95% CI, 68.8 to 83.0). MIC value ranged between 1.5 and 32 mg/l with an increasing trend in MIC50and MIC90with time. Mutations were found in acrR in one and rplV in two isolates of S. Typhi. No acquired mechanism for macrolide resistance was found. Interpretation & conclusions: Azithromycin could be considered as a promising agent against typhoid fever on the basis of MIC distribution in India. However, due to emergence of resistance in some parts, there is a need for continuous surveillance of antimicrobial susceptibility and resistance mechanisms. There is also a need to determine the breakpoints for S. Paratyphi A.
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Colorectal cancer is one of the most common malignant tumors in the digestive tract and the morbidity increase annually. Surgery is still the main method for treating colorectal cancer, supplemented by chemotherapy. However, chemotherapy resistance is the predominant cause for failed chemotherapy treatment against colorectal cancer. Exploring the resistance mechanisms against existing chemotherapy may be a key step for getting more effective chemotherapies against malignancies. The underlying mechanisms of resistance are complicated and interfered by numerous factors. This paper summarized the previous studies focusing on drug resistance mechanism, with the emphasize factors including mediation of membrane transporter proteins, abnormal changes in the activity of drug resistance-related transferase, apoptosis-related regulation, DNA repair, changes in microenvironment, and signal transduction pathways and activating transcription factors.
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As one of the most common pathogens in aquatic animals, Aeromonas hydrophila exhibits a wide range of pathogenicity. Due to factors like unreasonable use of antibiotics and horizontal gene transfer mediated by plasmids, many resistant strains of Aeromonas hydrophila were isolated from ready-to-eat seafood products in retail markets, supermarkets and restaurants. These strains carry many resistance genes. Therefore, it is essential to explore the key control points, and seek for prevention and control strategies so as to effectively alleviate antibiotic resistance. We review here the prevalence of drug resistance of Aeromonas hydrophila in China, and its main infection and resistance mechanisms, and the main means and strategies for reducing and preventing drug resistance. We also address further research directions and focus on drug resistance in Aeromonas hydrophila of the aquatic product.
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Animals , Aeromonas hydrophila , Anti-Bacterial Agents , Pharmacology , China , Epidemiology , Drug Resistance, Bacterial , Fish Diseases , Epidemiology , Microbiology , Fisheries , Fishes , Gram-Negative Bacterial Infections , Epidemiology , Microbiology , ResearchABSTRACT
Objective To investigate the chlorhexidine acetate-resistance in Klebsiella pneumoniae ( K. pneumoniae) clinical isolates and to analyze the possible mechanisms and molecular epidemiology of re-sistant isolates. Methods A total of 332 K. pneumoniae clinical isolates were collected in the First Affilia-ted Hospital of Wenzhou Medical University in 2015. Standard agar dilution was used to screen chlorhexidine acetate-resistant isolates. The minimum inhibition concentrations ( MIC) of chlorhexidine acetate to resistant isolates with and without the presence of carbonyl cyanide m-chlorophenyl hydrazone ( CCCP) , which was an efflux pump inhibitor, were analyzed. Efflux pump genes of cepA, qacE and qacΔE1 that carried by and ex-pressed in those isolates were detected by polymerase chain reaction ( PCR) and quantitative real-time PCR ( RT-qPCR) , respectively. The biofilm formation ability was measured by crystal violet staining. The homol-ogy among the chlorhexidine acetate-resistant isolates was investigated with multilocus sequence typing ( MLST) and pulsed-field gel electrophoresis ( PFGE) . Results Twenty-five K. pneumoniae strains were re-sistant to chlorhexidine acetate. The MIC values of chlorhexidine acetate for them were reduced by at least four-fold in the presence of CCCP. Strains carrying the genes of cepA, qacE and qacΔE1 accounted for 100％, 40％ and 40％, respectively. The expression of the efflux pump genes in the chlorhexidine acetate-resistant isolates was higher than that in the susceptible isolates. The biofilm formation ability of the chlo-rhexidine acetate-resistant isolates was better than that of the susceptible isolates. Furthermore, negative, weak-positive and positive biofilm formation ability was observed in four ( 16％) , 20 ( 80％) and one (4％) strains, respectively. The results of MLST and PFGE showed that the 25 chlorhexidine acetate-resist-ant isolates belonged to 19 different sequence types ( ST) with diverse PFGE patterns. Conclusions This study suggested that active efflux was the main mechanism of chlorhexidine acetate resistance in K. pneumoni-ae. The 25 chlorhexidine acetate-resistant K. pneumoniae strains possessed different biofilm formation ability and shared low homology.
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ABSTRACT Resistance profiles of houseflies (Gol-RR) collected from a field in Golmud city, Qinghai province, China, were determined for seven insecticides using topical bioassays. Resistance ratios of >1219.51, 153.17, >35.43, 6.12, 3.24, 1.73, and 0.86-fold were obtained for propoxur, cypermethrin, imidacloprid, indoxacarb, chlorpyrifos, fipronil, and chlorfenapyr, respectively, relative to a laboratory susceptible strain (SS). Synergism experiments showed that piperonyl butoxide (PBO), triphenylphosphate (TPP), and diethyl maleate (DEM) increased propoxur toxicity by >105.71, >7.88, and >5.15-fold in the Gol-RR strain, compared with 5.25, 2.00, and 1.39-fold in the SS strain, indicating the involvement of P450 monooxygenases, esterases, and glutathione-S-transferase in conferring resistance. Although cypermethrin resistance was significantly suppressed with PBO, TPP, and DEM in the Gol-RR strain, the synergistic potential of these agents to cypermethrin was similar in the SS strain, demonstrating that metabolism-mediated detoxification was not important for conferring resistance to cypermethrin in the Gol-RR strain. However, the three agents did not act synergistically with imidacloprid, indicating that other mechanisms may be responsible for the development of resistance to this insecticide. Acetylcholinesterase (AChE) activity was 13.70-fold higher in the Gol-RR than in the SS strain, suggesting the properties of the AChE enzyme were altered in the Gol-RR strain. Thus, rotation of chlorfenapyr insecticide with other agents acting through a different mode with minimal/no resistance could be an effective resistance management strategy for housefly.