New Opportunities to Combat Antibiotic Resistance——The Past and Present of Antibiotics

The discovery of antibiotics is one of the greatest achievements of modern medicine.Its application has saved hundreds of millions of infected patients, and it is still an irreplaceable anti-infective drug until now.

dark ages

Before the 20th century without antibiotics, people used cruel and ignorant methods such as maggot parasites, mercury therapy, and bloodletting to fight against infectious diseases. Even in 1942, William Osler's fourteenth edition of 'Principles and Practice of Medicine' In China, bloodletting is still used to treat pneumonia.Phlebotomy is based on an ancient medical theory: that the four body fluids (blood, phlegm, black bile, and yellow bile) must be in balance to maintain health.It was therefore believed that the infection was caused by excess blood, so venipuncture or arteriotomy was used, and leeches sucked blood for the purpose of exsanguination.People who were unable to control infection in that era could only linger in its shadow.

The hairdresser who is a part-time surgeon performs bloodletting therapy (sourced from the Internet)

dawn age

With the discovery and use of penicillin, more and more antibiotics have been developed one after another, and the medical field has thus entered the dawn age.Almost all classes of antibiotics today were discovered globally during this period¹, with the characteristics of high efficiency and low toxicity, they not only improve the ability of human beings to resist infection, but also inspire doctors to actively seek new treatment methods, such as surgery, organ transplantation and cancer chemotherapy, etc. (due to the high side effects of infection, these methods were not available before. OK)², so that the war between humans and infection has entered a new stage.It took China only 57 years to become the world's largest producer of penicillin. In 2001, China's penicillin production accounted for 60% of the world.However, this war without gunpowder is far from over.

times of crisis

As early as the dawn of mankind, Fleming, the discoverer of penicillin, warned that when anyone can buy penicillin in the market, trouble may come.The trouble Fleming warns of is precisely the emergence of resistance to antibiotics after they are used inappropriately.Today, it is less than a hundred years before antibiotics are used in clinical treatment, but according to the statistics of the World Health Organization, at least 700,000 people die from infections caused by drug-resistant bacteria every year, and if the current development trajectory is not changed, it is estimated that by 2050 This number will increase to 10 million deaths per year³.Fleming's warning has become a reality. When some infections caused by drug-resistant bacteria have no cure, it means that we will return to the terrible dark age.Antibiotic resistance is becoming a public health crisis.

The number of people who die from drug resistance each year (from the Internet)

In order to deal with the increasingly serious problem of antibiotic resistance, in May 2015, the 68th World Health Assembly formally adopted a resolution called 'Antimicrobial Resistance Global Action Plan', and the third week of November each year Declared as 'World Antibiotic Awareness Week'.Its goals are to raise global awareness of antibiotic resistance, strengthen surveillance and research and development, reduce the incidence of infectious diseases, optimize the use of antibiotics, and secure sustainable investment.Just because we cannot avoid drug resistance, we can only delay the process of drug resistance.The only way to slow down this process is to make the speed of drug resistance slower than the speed of new drug development through rational use of antibiotics, and to strengthen research on the mechanism of drug resistance to slow down the spread of drug resistance and reduce the demand for new drugs, so that we can fight against antibiotics in this battle. Leading the race for drug resistance.

The Era of Drug Resistance Gene Discovery Driven by NGS

Various types of antibiotic resistance threats have spread worldwide over the past few decades.Because drug-resistant genes are transferred horizontally between different bacteria in the form of plasmids, resulting in drug-resistant gene contamination, endangering the efficacy of many types of antibiotics, making clinical diagnosis and treatment difficult, including cephalosporins, carbapenems, β- Lactams and quinolone antibiotics have even begun to endanger the last line of defense in the treatment of CRE strain infection-polymyxin.In 2017, the Lancet magazine reported that mcr1-positive Enterobacteriaceae bacteria had begun to develop resistance to colistin².Therefore, in addition to continuing to search for new antibiotics or alternative drugs, infection control and surveillance measures have become one of the important multi-pronged methods of the public health system, and researchers and the pharmaceutical industry should follow this approach to overcome the threat of antibiotic resistance.For example, a combination of infection control and surveillance has contributed to the decline in the number of methicillin-resistant Staphylococcus aureus infections observed in US hospitals over the past decade⁴.The rapid development of gene technology provides a second-generation sequencing technology (NGS) that does not rely on culture and has higher sensitivity than traditional methods, providing more detailed information for the monitoring of antibiotic resistance epidemiology, and powerful Promoted the study of drug resistance genome, which facilitated the in-depth understanding of the mechanism and mode of transmission of antibiotic resistance.

The status of the global spread of plasmids carrying drug resistance genes²

Advances in sequencing technology have increased the availability of sequence data, and decreasing costs have made sequencing a viable tool for monitoring antibiotic resistance.Even combing sequencing data has become an important preprocessing step before the analysis of antibiotic resistance genes.The short fragments generated by sequencing are processed by bioinformatics methods. According to this method, the short fragments are assembled into continuous fragments (contigs), and then annotated after comparison with self-developed or public professional databases, or directly based on the fragments. analysis to analyze the determinants of antibiotic resistance by mapping them directly to reference databases.

Using NGS to Realize Correlation Analysis of Drug Resistance Genes 5

a Sample collection and sequencing

b Bioinformatics identification and assembly

c Analyze the data after the identification

NGS sequencing technology can not only be applied to drug resistance detection, but also plays a role that cannot be underestimated in the drug development process.Widespread application of NGS and functional metagenomic technologies will steadily increase our knowledge of the annotation of antibiotic resistance genes and their genetic background.Intelligent antibiotic resistance surveillance and drug design will be facilitated by considering specific resistance mechanisms and the risk of resistance transmission.

NGS Technology Helps in the Field of Drug Development and Drug Resistance Surveillance 2

PART 01

First of all, NGS technology is used in the research of drug-resistant genomes, which can help doctors adopt proactive clinical treatment strategies and help us win the 'arms race' between antibiotics and pathogenic bacteria.Second, NGS can focus on monitoring hotspots where drug-resistant genes may evolve or where horizontal gene transfer occurs: such as agriculture-related environments, hospitals, and sewage areas.Finally, PCR amplification and whole genome sequencing technology can screen out 'candidate' drug resistance genes and annotate them. These technologies combined with drug resistance function verification experiments can help us find drug resistance mechanisms as early as possible and take corresponding countermeasures.

PART 02

Extensive research into antibiotic resistance today enables us to understand and try to address the existing threat of antibiotic resistance.Yet despite our best efforts to develop new antibiotics, resistance will continue to develop and spread.Unless the current way is changed, it will become more and more difficult to establish and maintain a kind of status quo that can lead temporarily in this 'arms race'.As research into antibiotic resistance continues to advance, it is critical to have a defined, proactive approach to the identification, monitoring, and development of antibiotic therapy for antibiotic resistance.As a pioneer in the field of pathogenic microorganism detection in China, Difei Medicine launched Digankang DrSeq on the basis of Digankang. Using mNGS technology, it not only provides rapid, accurate and comprehensive pathogen identification services for clinics, but also provides supporting drug resistance genes Detection helps to reveal the mechanism of pathogen drug resistance, guide the selection of antibiotics, reduce the cost of patient treatment, and improve patient survival.

references

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2. Crofts TS, Gasparrini AJ, Dantas G. Next-generation approaches to understand and combat the antibiotic resistome[J]. Nature Reviews Microbiology, 2017.

3. Review on antimicrobial resistance. Antimicrobial resistance: tackling a crisis for the health and wealth of nations. O'Neill J editor.

4. Allen HK , Donato J , Wang HH , et al. Call of the wild: antibiotic resistance genes in natural environments[J]. NATURE REVIEWS MICROBIOLOGY, 2010, 8(4):251-259.

5. Malani PN . National Burden of Invasive Methicillin-Resistant Staphylococcus aureus Infection[J]. JAMA The Journal of the American Medical Association, 2014, 311(14):1438-1439.

6.M. Boochandani , AD Souza ，G. Dantas , Sequencing-based methods and resources to study antimicrobial resistance[J]. Nature Reviews Genetics,2019,20(6):356-370