Mechanisms of resistance to antibiotics

Microbial resistance to antibiotics is manifested by changes in antibiotic permeability, alteration of target molecules, enzymatic degradation of the antibiotics, and efflux of antimicrobials from the cytosol. Bacteria and other microorganisms use all of these mechanisms to evade the toxic effects of antibiotics. Recent research on the molecular aspects of these mechanisms, often informed by atomic resolution structures of proteins, enzymes and nucleic acids involved in these processes, has deepened our understanding of antibiotic action and resistance and, in several cases, spurred the development of strategies to overcome resistance in vitro and in vivo.     

Beta-lactamases and bacterial resistance to antibiotics

The efficiency of β-lactam antibiotics, which are among our most useful chemotherapeutic weapons, is continuously challenged by the emergence of resistant bacterial strains. This is most often due to the production of β-lactamases by the resistant cells. These enzymes inactivate the antibiotics by hydrolysing the β-lactam amide bond. The elucidation of the structures of some β-lactamases by X-ray crystallography has provided precious insights into their catalytic mechanisms and revealed unsuspected similarities with the DD-transpeptidases, the bacterial enzymes which constitute the lethal targets of β-lactams. Despite numerous kinetic, structural and site-directed mutagenesis studies, we have not completely succeeded in explaining the diversity of the specificity profiles of β-lactamases and their surprising catalytic power. The solutions to these problems represent the cornerstones on which better antibiotics can be designed, hopefully on a rational basis.     

Plasmid-determined streptococcal resistance to antibiotics]

The analysis of the genetic organization of the determinant ERLI by means of obtaining and studying the antibiotic sensitive mutants from the strain resistant to erythromycin and lincomycin provided experiment data in favour of the fact that inducable resistance to erythromycin and lincomycin determined by the plasmid might be defined by the same or closely linked genes.     

Mechanism of natural resistance to kirromycin-type antibiotics in actinomycetes

Abstract The sensitivity of intact cells and subcellular fractions of actinomycetes to kirromycin and pulvomycin was examined. These antibiotics block bacterial protein synthesis by acting on elongation factor Tu (EF-Tu). Two types of natural resistance were encountered in actinomycetes. Some strains were resistant to kirromycin and pulvomycin by virtue of inefficient cellular uptake of these drugs. In 3 strains, kirromycin resistance was attributable to a drug-insensitive EF-Tu. These 3 organisms produce kirromycin-type antibiotics: Streptomyces cinnamomeus, Streptomyces lactamdurans and Streptoverticillium mobaraense synthesize kirrothricin, efrotomycin and pulvomycin, respectively. In S. cinnamomeus and S. lactamdurans resistance to their own antibiotic is due to possession of a nonresponding EF-Tu factor, whereas pulvomycin resistance in Sv. mobaraense is more likely derived from the permeability properties of the cell envelope.     

Effect of mutations imparting resistance to antibiotics having different mechanisms of action on the virulence of Shigella flexneri

The study of the interaction between mutants of Sh. flexneri 2a and epithelial HeLa cells has revealed that in all cases the loss of virulence in the studied groups of mutants, resistant to antibiotics with different mechanisms of action (polymyxin M, mecillinam and neamin) was linked with the loss of the ability of bacteria to penetrate into epithelial cells. These changes are probably the result of disturbances in the structure of external membrane in polymyxin-resistant mutants, in the regulation of the penetration factor synthesis in mecillinam-resistant mutants, and in the translation process in neamin-resistant mutants.     

Short peptides conferring resistance to macrolide antibiotics

Translation of specific short peptides can render the ribosome resistant to macrolide antibiotics such as erythromycin. Peptides act in cis upon the ribosome on which they have been translated. Amino acid sequence and size are critical for peptide activity. Pentapeptides with different consensus sequences confer resistance to structurally different macrolide antibiotics, suggesting direct interaction between the peptide and the drug on the ribosome. Translation of resistance peptides may result in expulsion of the macrolide antibiotics from the ribosome. The consensus sequence of peptides conferring erythromycin resistance is similar to the sequence of the leader peptide involved in translational attenuation of erythromycin resistance genes, indicating that a similar type of interaction between the nascent peptide and antibiotics can occur in both cases.     

Reducing bacterial resistance to antibiotics with ultrasound

The effect of erythromycin on planktonic cultures of Psedomonas aeruginosa, with and without application of 70 kHz ultrasound, was studied. Ultrasound was applied at levels that had no inhibitory effect on cultures of Ps. aeruginosa. Ultrasound in combination with erythromycin reduced the viability of Ps. aeruginosa by 1-2 orders of magnitude compared with antibiotic alone, even at concentrations below the minimum inhibitory concentration (MIC). Electron-spin resonance studies suggest that ultrasound induces uptake of antibiotic by perturbing or stressing the membrane. This application of ultrasound may be useful for expanding the number of drugs available for treating localized infections by rendering bacteria susceptible to normally ineffective antibiotics.     

鲍曼不动杆菌对碳青霉烯类抗生素的耐药性分析

目的 了解鲍曼不动杆菌的耐药情况,并检测耐碳青霉烯类鲍曼不动杆菌的耐药基因,为指导临床合理用药、控制院内感染提供依据。方法 利用K-B法检测45株鲍曼不动杆菌临床分离株的耐药情况,通过改良Hodge试验、Carba NP试验和EDTA协同试验对多重耐药鲍曼不动杆菌的碳青霉烯酶进行表型检测,并采用PCR技术检测鲍曼不动杆菌携带OXA-23和NDM-1型耐药基因的情况。结果 45株鲍曼不动杆菌临床分离株中共筛出42株多重耐药菌株;利用改良Hodge试验和Carba NP试验检出36株碳青霉烯酶阳性菌株;采用PCR扩增出OXA-23,未扩增出NDM-1。结论 鲍曼不动杆菌耐药情况严重,且耐药基因OXA-23携带率高,治疗时应根据药敏试验结果合理用药。     

临床常见病原性细菌对抗生素的耐药性分析

目的了解长春地区部分医院临床分离的致病菌对抗菌药物的耐药情况。方法收集吉林大学中日联谊医院和长春中医药大学附属医院临床分离的致病菌,采用K—B法进行抗生素敏感性试验,参照CLSI2009年版的标准判断结果。结果从这两家医院共分离细菌447株,其中革兰阴性菌353株,占78．9％,革兰阳性菌94株,占21．1％。肠杆菌科细菌对氨苄西林的耐药率在70％以上,对庆大霉素的耐药率超过了50％,但对亚胺培南保持较高的敏感性（耐药率〈5％）。金黄色葡萄球菌和表皮葡萄球菌对红霉素耐药率分别为65．2％和82．1％,对万古霉素的耐药率较低,分别为4．5％和3．6％。非发酵革兰阴性杆菌对头孢他啶的耐药率超过50％,铜绿假单胞菌对氨曲南的耐药率达到了62．9％,对他唑巴坦复合制剂、亚胺培南、美罗培南和阿米卡星较为敏感,而鲍曼不动杆菌对各类抗生素的耐药率都较高。结论细菌对抗生素的耐药性仍表现出增长趋势,加强细菌耐药性的检测,对于指导临床正确、合理使用抗生素,减少耐药菌的产生和传播具有重要意义。     

益生菌对16种抗生素的耐药性分析

目的评估市场常见益生菌对临床常用抗生素的体外耐药情况,为临床预防抗生素相关性肠道菌群紊乱和抗生素相关性腹泻提供参考。方法分离培养9种益生菌制剂中的20株益生菌,采用浓度梯度试条法(E-test)测定益生菌对16种抗生素的最低抑菌浓度(MIC)。结果细菌类益生菌对一些口服抗生素敏感,其中枯草芽胞杆菌、保加利亚乳杆菌、长双歧杆菌、婴儿双歧杆菌和嗜热链球菌对12种以上的抗生素敏感;屎肠球菌只对5种抗生素敏感,而真菌类益生菌如布拉酵母CNCM I-745则对16种抗生素均具有耐药性。结论细菌类益生菌和真菌类益生菌表现出不同的抗生素敏感性,在临床预防和治疗抗生素相关性腹泻时应注意益生菌与抗生素的合理使用。