(1) Foreword: The continuous development of chemotherapeutic drugs starting with sulfonamides and penicillin has achieved remarkable results in the treatment of infectious diseases. However, with the clinical application of new drugs, new problems such as changes in clinical isolates and drug resistance have emerged. One of the reasons for the rapid increase of drug-resistant bacteria is that most of the drug-resistant genetic factors are transposons, so the translocation from one inheritance to another is not affected by drug selection, and the translocation rate is high. Once the drug-resistant genetic factor is transferred to cytoplasmic inheritance, cytoplasmic inheritance becomes drug-resistant genetic factor, which makes its bacteria (species) resistant through binding conduction. In addition, the chemical structure of drugs, such as β -lactam antibiotics, aminoglycoside antibiotics and tetracycline antibiotics, and their basic skeleton fixation are also the reasons for the increase of drug-resistant bacteria. The mechanism of drug resistance is mostly enzyme-induced drug inactivation and hydrolysis. The genetic factor responsible for producing this enzyme is prone to mutation, which can expand its matrix specificity and show cross-resistance to drugs with the same basic skeleton on many occasions. In contrast, there are also drug-resistant bacteria produced by chromosomal genetic factors. It takes a long time to produce this drug-resistant strain, and the probability of transferring drug resistance to other strains after production is also very low. Therefore, the drugs of drug-resistant bacteria produced by chromosomal genetic factors can maintain stable clinical efficacy for a long time, and pyridone carboxylic acid or quinolones synthetic antibiotics are the representatives of such drugs. For the above reasons, it has attracted much attention today. In the following, the structure-activity relationship mechanism and drug resistance mechanism of new quinolones in quinolones synthetic antibiotics are expounded. (II) Structure-activity relationship: Since Nalidixic acld NA was published in 1962, many similar compounds of this kind of drugs have been chemically synthesized, and their structure-activity relationship is now described. Among them, miloselta has attracted much attention because of its strong antibacterial activity and good pharmacokinetics, such as MLX, PA, PPA and cinoxacin. The basic skeletons of these compounds are naphthyridine, quinoline, pyridopyrimidine and porphyrin. The structure required to produce antibacterial effect is considered to be a pyridone carboxylic acid moiety containing carbonyl, carboxyl and nitrogen atoms. Therefore, these drugs are collectively referred to as pyridone carboxylic acid synthetic antibiotics. However, norfloxacin NFLX and enoxacin ENX, published in 1978 and 1979, respectively, introduced fluorine into quinoline ring and naphthyridine ring, which significantly improved the antibacterial effect, expanded antibacterial spectrum, stable metabolism and good tissue transport compared with the original pyridone carboxylic acid antibiotics. Then, ofloxacin. OFLX) published in 198 1, Ciprofloxaein CPFX) published in 1983. Up to now, the basic skeleton of these new pyridone carboxylic acid compounds is condensed compounds of pyridone ring and other cyclic structures. In a narrow sense, it is a compound with quinoline skeleton, so pyridone carboxylic acid was renamed quinolone. Up to now, almost all the published papers containing pyridone carboxylic acid antibiotics are quinolones. These compounds are also referred to herein as quinolones. Quinolone antibiotics synthesized from nalidixic acid have attracted much attention as a new generation of quinolone antibiotics by introducing fluorine atoms into the mother nucleus, expanding the antibacterial spectrum, enhancing the antibacterial efficacy and improving the in vivo kinetics. The structure of pyridone carboxylic acid drugs is shown in Figure 2 of the last issue of the journal [Clinical Instructions for Quinolones]. As the basic skeleton, there is a pyridone carboxylic acid structure located on the right side of the bicyclic ring. If NA, PA, PPA, MLX and CINX are the first generation, then the second generation of new quinolones ENX and tofloxacin ('TFLX') have naphthyridine mother nuclei, NFLX, OFLX, CPFX and lomefloxacin LFLX have quinoline mother nuclei, and fluorine atoms are introduced into six positions of the mother nuclei. The main antibacterial activities of these drugs are shown in table 1. Although the first generation of NA and PPA showed antibacterial activity against Gram-negative bacteria, their activity against Gram-positive bacteria was weak. In contrast, NFLX, OFLX, ENX, CPFX, LFLX and TFLX of new quinolones expanded their antibacterial spectrum, which not only showed antibacterial activity against gram-positive bacteria, but also significantly enhanced their antibacterial effects. After fluorine atom was introduced into the 6-position of NA with naphthyridine mother nucleus, the antibacterial effect on Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa was enhanced, and the antibacterial effect was further enhanced after piperazine group was introduced into the 7-position. This is because the introduction of these substituents enhances the inhibition of the target DNA of quinolones-gyr-ase, thus enhancing the antibacterial effect. NFLX, OFLX and CPFX containing quinoline mother nucleus also enhanced the antibacterial effect. In addition, compared with NA, the new quinolones have moderately enhanced hydrophilicity, good permeability to Gram-negative bacteria, eliminated the permeability barrier caused by lipopolysaccharide, and expanded and enhanced their antibacterial spectrum and antibacterial effect. Other substituted fluorine such as halogen was introduced into the 6-position of quinoline mother nucleus, and its antibacterial effect was studied. As a result, it is found that these elements can enhance the antibacterial effect more than fluorine. The introduction of 8-substituent was also studied. As shown in the figure, there is not much difference in antibacterial effect between quinoline skeleton with X=CH and naphthyridine skeleton with X=N, but the introduction of fluorine and chlorine enhances the antibacterial effect on Gram-positive bacteria. According to the study of 1 substituent, cyclopropyl showed the strongest antibacterial activity. The substituent at 1 has such a great influence on antibacterial activity, which shows that the interaction between drugs and target sites is closely related. From the study of 7- substituents, if aminopyrrolidine is introduced into TFLX, it can enhance the antibacterial effect against Gram-positive bacteria more than piperazine groups in NFlX and CPFX. Above, focusing on new quinolones, the functions of substituents at different positions in the mother nucleus were introduced. Of course, only the relationship between antibacterial effect and structure is introduced. As an antibacterial agent, its functional characteristics are closely related to the physical properties of the whole compound, and there is a hydrophilic problem. The study on the relationship between partition coefficient and antibacterial activity shows that the compounds with partition coefficient close to-1 have better antibacterial activity. (III) Antibacterial effect of quinolones on clinical isolates: The MIC90 of clinical isolates collected from quinolones 1986~ 1988 was counted, and the results were as follows. For gram-negative bacteria, the antibacterial effects of new quinolones are: CPFX > TFLX > OFLX, AM-833 > LFLX, ENX, NFLX；; ; For gram-positive bacteria, TFLX is the strongest, followed by OFLX > CPFX > AM-833. TFLX also showed strong antibacterial activity against Bacteroides fragilis and Clostridium perfringens. There are few reports about the antibacterial effects of new quinolones on other microorganisms. It is reported that new quinolones have very strong antibacterial effects on Campylobacter, Legionella, Micrococcus, Chlamydia and Mycobacterium tuberculosis. New quinolones have been used in clinic for more than 5 years. With the increase of dose, the emergence of new quinolone-resistant bacteria has attracted people's attention. Japan is conducting an investigation in this regard. The investigation results in the past six years show that Pseudomonas aeruginosa, Serratia marcescens and Staphylococcus aureus account for 10 ~ 17%, 25 ~ 34% and 2 ~ 5% respectively. Drug-resistant bacteria were also isolated from bacteria taking quinolones, and the drug resistance rate fluctuated greatly among strains. The author studied the different inspection items of 123 strains of Serratia marcescens isolated from 1987 and the isolation rate of drug-resistant bacteria in different hospitals. The results showed that the isolation rate of drug-resistant bacteria varied greatly in different inspection items and hospitals. In addition, Serratia marcescens strains sensitive to quinolones were randomly selected to study the occurrence rate of drug-resistant strains in vitro. The results showed that the frequency difference of different strains was 10 ~ 1000 times. Therefore, the survey results reflect the mode of administration (whether it is long-term administration) and the type of patients (whether they are patients in large hospitals; Or inpatients or outpatients), the proportion of drug-resistant bacteria varies greatly due to the different isolation conditions of bacteria in many occasions. Therefore, in order to grasp the development trend of drug-resistant bacteria, it is necessary to fully study the background of clinical isolates. (4) Mechanism of action of quinolones: The essence of genetic factor is deoxyribonucleic acid (DNA). The length of bacterial chromosome DNA with double helix ring structure is about 1 .500μ m. It is conceivable that if such a huge substance is to be contained in a bacterium with a length of only about1micron, the DNA must be folded regularly in the form of high-order structure. After the bacteria were lysed under very mild conditions, the chromosomal DNA was observed with a microscope. As a result, DNA with dense ring-shaped high-order spiral structure centered on a certain point can be captured. With the division of bacteria, the process of correctly distributing chromosomal DNA to daughter cells is very complicated. Many enzymes are needed. When DNA is distributed in daughter cells, some advanced spiral structures are partially unwound in turn, and the DNA exactly the same as the mother DNA is synthesized again. At the same time, the untied DNA re-forms the original advanced spiral structure. This is DNA replication, which is called DNA supercoiled or uncoiled (relaxed). The replication of genetic information in DNA molecules, transcription into RNA (ribonucleic acid) and rearrangement of other genetic factors require a variety of enzymes to polymerize into bases in DNA molecules. In some topological DNA molecules, bases can interact with enzymes, while others cannot. For example, the super-spiral structure can make the double helix of the circular double-stranded reverse winding. Rewinding makes the bases in the helix outward, so that they are acted by enzymes. The enzyme involved in the transformation of DNA supercoiled or uncoiled structure is DNA gyrase. DNA gyrase is a protein with a molecular weight of about 400,000. This protein consists of two subunits (or subunits), called A and B. The formation of supercoils requires adenosine triphosphate (ATP). The energy released during ATP decomposition is the driving force for the formation of supercoils. In the absence of ATP, although the speed is very slow, DNA gyrase can untie the negative supercoiled loop. In the presence of DNA gyrase, it can be found that subunit A binds to the two 5' ends of the cleavage site when the loop is cleaved. This shows that the ends produced when DNA is cut off prevent each other from leaving. The two 5' ends of the cleavage site are bound to subunit A, and the two subunits A are bound to subunit B. The DNA fragment of DNA gyrase is about 150 base pairs, and most of the bound DNA fragments are wrapped around the enzyme. Quinolones such as NA can inhibit DNA gyrase. The study on the inhibitory effect of drugs on DNA gyrase showed that the 50% inhibitory concentration (ID50) of cpfxcpfx was 1.0μg/ml, OFLX3. 1μg/ml, NFLX 2.4μg/ml, PPA 156μg/ml, and new quinolones. In addition, the 50% inhibitory concentrations of CPFX, OFLX, NFLX and PPA were 6.65438 0.7 μ g/ml, 0.34 μ g/ml and 0.5 μ g/ml respectively. Because the inhibitory concentration of DNA gyrase is close to MIC value, it shows that the inhibitory effect of quinolones is to inhibit the activity of DNA gyrase on relaxed DNA. (V) Permeability of drugs in bacteria and permeability of pores: Intracellular permeability of NA and PA invades bacteria through lipopolysaccharide (LPS), and new quinolones invade bacteria through pores. Generally speaking, through holes are holes through which water-soluble substances can easily pass. The distribution coefficient of new quinolones is more hydrophilic than that of NA and PA, from which we can also imagine the antibacterial strength of new quinolones. The amount of new quinolones entering bacteria is 30 ~ 50 times that of NA. This also shows that the permeability of new quinolones in bacteria is excellent. (VI) Drug resistance mechanism: In vitro studies show that sodium-tolerant bacteria reduce the inhibition of drugs on DNA gyrase due to the variation of gyrase A or gyrase B, that is, the change of DNA subunit A or B. Through MIC comparison, it can be found that gyrase A variant is resistant to various quinolones, while gyrase B variant varies from drug to drug, even if it has drug resistance, it is weak. The isolation rate of sodium-tolerant bacteria in vitro is 10-7~ 10-8. Of course, the isolation frequency varies with strains and strains. For example, Serratia marcescens strains sensitive to quinolones were randomly selected to study the isolation rate of drug-resistant strains. Therefore, its frequency is 10-4~ 10-8. The difference in the frequency of this drug-resistant bacteria reflects the isolation rate of quinolone-resistant bacteria in clinical isolates. The drug resistance mechanism of four quinolone-resistant strains isolated from nature was studied. Firstly, the DNA gyrase of drug-resistant bacteria was purified and divided into subunit A (Ar) and subunit B (Br). Then, A subunit (As) and B subunit {Bs} were isolated from sensitive bacteria, and their respective subunits were formed in vitro to study how quinolones inhibited the gyrase activity of each DNA. Among the sodium-tolerant bacteria isolated from clinic, the drug resistance value is not very high, and some of them also show moderate MIC. Among them, some strains showed resistance to β -lactam antibiotics and aminoglycoside antibiotics. Therefore, it can be considered that the mechanism of drug resistance is caused by pore variation. Of course, detailed analysis is still a future research topic. (7) Other problems: Recently, as one of the functions of drugs, "PAE" has attracted special attention. The so-called PAE refers to the effect of drugs on bacteria in a certain period of time, before the bacteria return to the same state as without drugs after the drugs are eliminated. Here, PAE intensity is expressed by the time required for bacteria to return to normal. Aminoglycosides, chloramphenicol, rifampicin, tetracycline, etc. There is PAE effect, β -lactam antibiotics, especially Gram-positive bacteria, and CPFX of new quinolones also have PAE effect. PAE refers to more than one drug targeting site, which may have a second or third action site, or refers to the affinity strength between the main targeting site and the drug. Include new quinolone antibiotics, and the PAE of drugs changes with the dose, so PAE is important when considering the in vivo effect, especially the dose. Conclusion: The structure-activity relationship of new quinolones has gradually become clear. In addition, it has many characteristics, such as broad antibacterial spectrum, strong antibacterial effect, specific mechanism of action, good intracellular permeability and so on. It should be said that it is a kind of drug worthy of attention.