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Innovative and Speedy Discovery and Development of Antibiotics against Multi-Drug Resistant Infectio
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| 작성일 | 2017-08-01 | 조회수 | 4,153 |
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Innovative and Speedy Discovery and Development of Antibiotics against Multi-Drug Resistant Infectious Diseases
- 글 이희민(Heemin Rhee)
- GPKOL위원
경력사항
- 2011~現 Health Research International 대표
- 現 한국보건산업진흥원 GPKOL 위원(임상, R&D기획 분야)
학력사항
- 1973-1976 위스콘신 의과대학(University of Wisconsin Medical School), 약리학 박사 후 과정
- 1970-1973 오하이오 주립대 의과대학, 약리학 박사
Abstract
Korea has rich tradition in the research and development of antibiotics that started from LG’s Factive and Donga-ST’s Tedizolid. But, now our antibiotic industry must face many dreadful multi-drug resistant infectious diseases (MDRID) as a direct result of antibiotic misuses and abuses. To speed up the development of mechanistically innovative antibiotics, many countries including WHO are working together for the acceptable solution of the common international task. In this short report, the author described the current magnitude of MDRID in the U.S. and other international community. Particularly, the innovative antibiotic research at the U.S. National Institute of Health (NIH) and other organizations is briefly presented while the U.S. Food and Drug Administration’s initiation of Qualified Infectious Disease Products (QIDP) Designation was commented briefly in the conclusion section for the Korean pharmaceutical companies.
Table of Contents
- I.Introduction
-
II.Main Subject
- 1.Classes of Antibiotics and their Development for MDRID
- 2.Initiation of Antibiotic Resistance
- 3.Drugs and Management against Multi-Drug Resistant Bacteria
- 4.Clinical Antibiotic Researc
- 5.Worldwide Efforts for New Antibiotic Development
- a.Synthetic Biology Techniques for Antibiotic Production
- b.Monoclonal Antibodies for Gram-negative Bacteria
- c.New Innovative Technique of CRISPR for the Research and Development of Antibiotic-resistant Bacteria
- III.Conclusion
- IV.Figures and Tables
- V.References
I.Introduction
In the U.S., at least 2 million people become infected with bacteria that are resistant to antibiotics and 23,000 people die each year as a direct result of these infections. Over 250,000 people become infected with Clostridium difficile in the U.S. annually and the bacteria alone kills 14,000 Americans a year. Three hazard bacteria are Clostridium difficile (C. difficile), Carbapenem-resistant Enterobacteriaceae (CRE) and Drug-resistant Neisseria gonorrhoeae (cephalosporin resistance). To our surprise, the deaths related to antibiotic resistance happen in our healthcare settings such as hospitals and nursing homes (Healthcare Associated Infection).
U. S. Congress concerns about the lack of antibiotics in development, particularly, against the MDRID. Centers for Disease Control and Prevention (CDC) collected relevant information and FDA initiated Qualified Infectious Disease Product (QIDP) Designation to speed up the discovery and development of agents against antibiotic resistant infections. The FDA also often allows additional 5–7 years of market exclusivity for QIDP designation o top of the traditional Priority and/or Fast-Track Designations, etc. However, big pharma is not willing to invest antibiotic industry due to short-term use, low price standards and poor returns including and costly phase-III trials that have onerous recruitment requirements needed to fulfill the non-inferiority conditions currently mandated by FDA.
Sally Davies, England’s Chief Medical Officer, published a five-year Antimicrobial Resistance Strategy, of which plan promotes both the responsible use of antibiotics and development of new diagnostics, therapeutics and antibiotics for use in the medical field. World Health Organization and Trump administration at the end of 2016 and early 2017 urging continued support for antibiotic innovation programs. They raised awareness to implement the Strategies to Address Antimicrobial Resistance (STAAR) Act, of which legislation is comparable to England’s Antimicrobial Resistance Strategy. The FDA and CDC, which has noted the appearance of drug-resistant bacteria in new strains, are also participating in campaigns for increased attention to this research.
Historically Korean pharmaceutical companies are well-known in discovering and development of antibiotics. LG developed Factive that was the first Korean drug which was approved by the U.S. FDA in 2003 as an antibiotic. Subsequently, Donga-ST initially discovered Sivextro (tedizolid), which was developed further by Trius and Cubist Pharmaceutical companies as shown (Tab. 1) below so that it met the requirements of the U.S. FDA’s NDA in 2014. Thus, the purpose of this paper is to review our current scientific status of MDRID in the U.S., which will contribute to the production of safe and effective new innovative antibacterial agents in Korea for the worldwide markets.
II.Main Subject
1.Classes of Antibiotics and their Development for MDRID
A variety of pharmaceutical products are effective against infectious diseases: they are antibiotics, antifungals, anti-infectives, anti-malarials, anti-parasitics, antivirals and various vaccines. The antibacterial drug market covers the drugs used in the prophylaxis and treatment of bacterial infections. There are over 1400 products in active development for the antibacterial drug market, with majority of products being small molecules. Penicillins represent one of classic, but significant scientific event in human microbiology and pharmaceutical history. They interfere with the synthesis of bacterial cell wall as their molecular mechanism of action.
Many beta-lactams (cephalosporins, carbapenums, monobactams) and vancomycin and bacitracin inhibit the creation or repair of the cell wall while others interfere with the cell's ability to make protein or replicate DNA, which share with the similar molecular mechanistic action of penicillins. Quinolones affect nucleic acid synthesis while polymyxins are cell membrane disrupters. Rafamycins interfere with RNA polymerase as shown (Fig. 1). Many other antibiotics interfere with protein synthesis by acting on either 50S or 30S subunit. They are macrolides, clindamycin, linezolid, streptogramins, oxazolidinones, chloramphenicols, amimoglycosides and tetracyclines. We also have folate synthesis inhibitors like sulfonamides and trimethoprim, as one of oldest antibiotic agents.
2.Initiation of Antibiotic Resistance
Antibiotic resistance is due to frequent abuse of sub-lethal drugs, environmental or the abuse of antibiotics in agriculture, and the antibiotic- and target-modifying enzymes. Indeed, Dr. Alexander Fleming warned the public that penicillin was being misused 70 year ago. Right antibiotic, right dose, right duration are relevant when the fundamental problem is a misdiagnosis. Unnecessary antibiotic use in patients with asymptomatic bacteriuria facilitates the emergence of multidrug-resistant organisms such as Clostridium difficile infections.
Antibiotic resistance is spreading faster than the introduction of new drugs into clinical practice. Most antibiotics were produced by screening soil microorganisms, but this limited resource of cultivable bacteria. Uncultured bacteria make up 99% of all species in external environments, and are an untapped source of new antibiotics. New methods to grow uncultured organisms by cultivation in situ or by using specific growth factors. A new antibiotic, teixobactin, from uncultured bacteria, which inhibits cell wall synthesis by binding to a highly conserved motif of lipid II (precursor of peptidoglycan) and lipid III (precursor of cell wall teichoic acid).
As to the U.S. NIH recent progress, a simple blood test that analyzes patterns of gene expression to determine if a patient’s respiratory symptoms likely stem from a bacterial, viral infection, or no infection at all. In contrast to standard tests of respiratory syncytial virus (RSV) or the influenza virus, for instance, the new strategy tests for gene expression in the bloodstream, which differ depending on whether a person is fighting off a bacterial or a viral infection.
Science Translational Medicine described that Duke University collected blood samples from 273 people who came to the emergency room (ER) with signs of acute respiratory illness. Standard diagnostic tests showed that 70 patients arrived in the ER with bacterial infections and 115 were battling viruses. Another 88 patients had no signs of infection, with symptoms traced instead to other health conditions. Some of those patients might take antibiotics without a careful consultation with their physician, which is antibiotic abuse that may incubate drug resistant infectious bacteria.
3.Drugs and Management against Multi-Drug Resistant Bacteria
There is growing global recognition that the continued emergence of multi-drug resistant bacteria poses a serious threat to human health. Action plans released by the WHO and governments of the UK and USA in particularly recognize that discovering new antibiotics, particularly those with new modes of action, is one essential element required to avert future catastrophic pandemics. Scientists reviewed lists the 30 antibiotics and two β-lactamase/β-lactam combinations first launched since 2000, and analyzes in depth seven new antibiotics and two new β-lactam/β-lactamase inhibitor combinations launched since 2013. The development status, mode of action, spectra of activity and genesis (natural product, natural product-derived, synthetic or protein/mammalian peptide) of the 37 compounds and six β-lactamase/β-lactam combinations being evaluated in clinical trials.
So-called ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.) organisms are of particular concern because they are responsible for many serious infections in hospitals. Antibacterial researchers have struggled to identify new molecules with meaningful cellular activity, especially those effective against multi-drug resistant Gram-negative pathogens. This difficulty ultimately stems from an incomplete understanding of efflux systems and compound permeation through bacterial membranes. Phenotypic screening efforts carried out at AstraZeneca over the past decade, discusses some of the subsequent chemistry challenges and concludes with a description of new approaches comprising a combination of computational modelling and advanced biological tools which may pave the way towards the discovery of new antibacterial agents.
To combat multi-drug resistant bacteria, researchers are searching for new classes of antibiotics that work by different mechanisms. Spirohexenolide A is an antibiotic known to be effective against Methicillin-resistant Staphylococcus aureus (MRSA), which disrupts the membranes of target bacteria (Proc Natl Acad Sci U S A. 2013 Sep 17). New antibiotic development depends on its mode of action, spectra of activity, historical discovery and origin of the drugs such as natural product (NP), NP-derived, synthetic (S) or protein/peptides.
Bacterial cytological profiling (BCP) is a fluorescene-based means of determining a candidate antibiotic’s mode of action that can identify the cellular pathways, compared to traditional methods such as radiolabeling assays or transcriptional profiling. BCP (Linnaeus Bioscience) needs just 2 hours while old methods took 2-6 months to look at different parts of bacterial cell. The mode of action can be analyzed by the target bacterial cell’s shape and appearance under fluorescence microscopy with different stains. Besides mechanistic studies, clinically applicable translational research is badly needed along with public-private partnership such as the combined resources of the Bill & Melinda Gates Foundation, Janssen Pharmaceuticals, and the TB Alliance, which has now produced bedaquiline, the first new FDA-approved drug for tuberculosis in the past 40 years.
4.Clinical Antibiotic Research
Distinguishing between resistance, tolerance and persistence to antibiotic treatment unlike resistance, which is commonly measured using the minimum inhibitory concentration (MIC) metric, tolerance is poorly characterized, owing to the lack of a similar quantitative indicator. A framework for classifying the drug response to bacterial strains, according to the definition, that is based on the measurement of the MIC together with a recently defined quantitative indicator of tolerance, the minimum duration for killing (MDK), as shown (Fig. 2) below.
Whole-genome sequencing on isolates obtained from all symptomatic patients with C. difficile infection identified in health care settings or in the community in Oxfordshire, United Kingdom. They compared single-nucleotide variants (SNVs) between the isolates, using C. difficile evolution rates estimated. The first and last samples obtained from each of 145 patients, with 0 to 2 SNVs expected between transmitted isolates obtained less than 124 days apart, on the basis of 95% prediction interval.
Medical devices can be used for anti-infective purposes. For example, Ultraviolet-C (TRU-D UVC) light for drinking water and air sanitation. Lumalier (Memphis) is 5’5” Robot UVC germicidal irradiation device that kills MRSA in 25 min while C. difficile will takes 45 minutes. Xenex Disinfection Services (San Antonio, TX, USA) uses mercury gas vapor lamps and pulsed xenon, which kills C. difficile takes 5 minutes.
5. Worldwide Efforts for New Antibiotic Development
By March of 2017, 41 antibiotics were undergoing clinical trials: two NDA submissions, 15 Phase 1 trials, 13 Phase 2, and 11 Phase 3. Many new substances are expected to act against resistant gram-negative ESKAPE pathogens and CDC "urgent threat" pathogens. None of these drugs are guaranteed to qualify beyond trials. Experiments in 2015 demonstrated persistent microbes being exterminated by teixobactin, isolated from an uncultured bacterium E. terrae. In the laboratory setting, teixobactin bound to conserved motifs of lipid II and III, inhibiting the synthesis of cell walls in bacteria and causing cell lysis. Teixobactin proved effective against pathogens already displaying drug-resistance. Results predict that it would take 30 years for bacteria to develop resistance against this class of antibiotics.
a.Synthetic Biology Techniques for Antibiotic Production
Nonribosomal peptides are normally produced by bacteria and fungi, forming the basis of most antibiotics today. Pharmaceutical companies have long experimented with nonribosomal peptides to make conventional antibiotics. The rise of antimicrobial resistance means there is a need to use genetic engineering techniques to find a new range of antibiotics from bacteria and fungi. Baker's yeast cells on the other hand are easy to genetically engineer. Scientists can simply insert DNA from bacteria and fungi into the yeast to carry out experiments, offering a viable new host for antibiotic production research. The rise of synthetic biology methods for yeast is expected to allow researchers to make and test many new gene combinations that could produce an entire new range of new antibiotics. They have only been working with yeast in this context for a handful of years, but now that scientists developed the blueprint for coaxing yeast to make penicillin. Re-engineered yeast cells to develop new forms of antibiotics and anti-inflammatory drugs from nonribosomal peptides might be a routine procedure.
b.Monoclonal Antibodies for Gram-negative Bacteria
The Bill and Melinda Gates Foundation awarded Achaogen $10.5 million in grant funding to support the identification of monoclonal antibodies (mAbs) against multidrug-resistant Gram-negative bacteria. The initial grant will fund Achaogen’s program to discover mAbs against Acinetobacter baumannii, which is the major cause of neonatal sepsis. If this project is successful, Achaogen may receive future grants from the Gates Foundation for additional antibody discovery and development programs.
Plazomicin is an aminoglycoside antibiotic. Neonatal sepsis remains one of the deadliest conditions afflicting newborns globally. The successful development of simple and sustainable prophylactics and therapeutics would decrease neonatal mortality in developing countries. Achaogen's lead candidate plazomicin is an aminoglycoside antibiotic that has been evaluated in two Phase III trials, evaluating plazomicin in complicated urinary tract infection and combating antibiotic resistant enterobacteriaceae (CARE), for treating serious bacterial infections caused by multi drug resistant Enterobacteriaceae.
Vaccines are also well established within the market, and accounts for approximately 25% of the pipeline. Drugs for the prevention of bacterial infections are typically vaccines which help to train the body’s immune system to fight off bacterial infections caused by specific bacterial strains. Currently several prophylactic monoclonal antibodies are now in the pipeline and may impact the market.
c.New Innovative Technique of CRISPR for the Research and Development of Antibiotic-resistant Bacteria
When a bacteriophage infects archaea or bacteria, the clustered regularly interspaced short palindromic repeats (CRISPR) system stores pieces of phage DNA as a type of immune memory. The cell can then transcribe guide RNA from the stored sequence, pair it up with a Cas enzyme, and set the duo loose to surveil the cell for matching invaders. When the RNA finds its match, Cas cuts the phage DNA, preventing it from replicating. Scientists can deliver specific guide RNAs to bacteria and provoke the native CRISPR system to cut plasmids carrying antibiotic resistance genes to prevent their spread or even to cut up the cell’s own chromosome, selectively eliminating certain bacteria from a population.
Scientists could induce cell death either with native CRISPR systems or by importing the CRISPR components into cells, and that cell death resulted regardless of where in the genome they targeted. This approach enabled to specifically eliminate certain bacteria from mixed cultures and titrate the level of cell death, from which they saw potential for developing this CRISPR-based method as a new class of antibiotics.
With CRISPR-phages, these therapies can be developed and optimized against more traditional pharmacokinetic parameters, such as persistence, time, and concentration at the site of infection. While CRISPR carried in phages seems ideal for treating bacterial infections, all antimicrobial agents exert strong selective pressures, raising the possibility that bacteria will develop resistance. Since CRISPR is so versatile, however, researchers may be able to keep ahead of the changes and quickly redesign new generations of CRISPR antibiotics to outwit bacterial evolution.
III.Conclusions
Antibiotic research deals with one of traditional and broad paradigms of human investigation aiming for freeing ourselves from multiple life-threatening infectious diseases. Multi-drug resistant infectious bacteria that we invited by antibiotic abuse kill human beings around the world. Unfortunately, the worldwide antibiotic resistance is spreading much faster than the introduction of new anti-infective drugs into clinical practice. Naturally, in 2012, the U.S. FDA began offering Qualified Infectious Disease Products (QIDP) Designation, based on the U.S. Generating Antibiotic Incentive Now (GAIN) Act. The QIDP designation allows for the FDA’s expedited review and five extra years of exclusivity. Indeed, four new antibiotics were approved by the FDA under QIDP in 2014.
We briefly reviewed the critical issues of multi-drug resistant bacterial infections, their basic and clinical impacts including the innovative new methodology and techniques to produce effective pharmaceutical agents that fight against the multi-drug resistant bacteria. Besides, the FDA has many expedited programs such as Fast Track, Accelerated, Priority, Orphan Drug, Breakthrough and Enrichment Therapy Designations for serious diseases with unmet medical needs, as shown (Tab. 2) below. Korean pharmaceutical companies can follow up the excellent footsteps of Factive and Sivextro discovery and development through the effective international scientific collaborative research and development for the worldwide markets.
IV.Tables and Figures
Fig.1
Fig.2
Fig.3
V.References :
- Brauner, A. et al: Nature Reviews Microbiology 14, 320–330 (2016)
- Butler et al: J. Antibiotics 70 (2017)
- Fischbach, MA and CT Walsh: Science 325 (5944), 1089-1093 (2009)
- Lewis, K.: Nature Reviews Drug Discovery 12, 371–387 (2013)
- Silver L.: Biochemical Pharmacology 71(7), 996-1005 (2006)
- Tommasi, R. et al: Nature Reviews Drug Discovery 14, 529–542 (2015)
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