Теиксобактин Большие надежды на будущее

Expert Review of Anti-infective Therapy

Volume 17, 2019 — Issue 1

Editorial

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1. Introduction

In 2015, a screen of bacterial strains produced a novel antibiotic with broad antimicrobial activity known as teixobactin [ 1 ]. The compound was identified using a new method to grow uncultured organisms by cultivation in situ, and was found to inhibit cell wall synthesis by binding to a highly conserved precursors such as lipid II, lipid III, and undecaprenyl pyrophosphate [ 2 ]. Properties of the compound, which was obtained from a grassy field in Maine, suggested that developing resistance might be difficult [ 3 – 5 ]. Subsequent work in a murine model indicated that teixobactin might be a promising therapy in humans, including patients with methicillin-resistant Staphylococcus aureus (MRSA) [ 6 ]. This paper reviews the discovery and development of teixobactin and its analogs, and explores how they may serve as an example for other novel compounds that are in development to address the expanding problem of antimicrobial drug resistance.

2. Discovery

A multichannel device, known as the iChip, was developed to simultaneously isolate and grow uncultured bacteria (those that cannot grown under normal laboratory conditions), which have been identified as a promising source of novel antimicrobial agents [ 7 , 8 ]. With this platform, a soil sample is diluted so that approximately one bacterial cell is delivered to a given channel, after which the device is covered with two semi-permeable membranes and returned to the soil. Diffusion of growth factors through the membrane enables growth of uncultured bacteria, which account for approximately 99% of all species, in their natural environment.

In 2015, Ling and colleagues reported a new way to grow previously uncultivable organisms by providing growth factors [ 2 ]. Thousands of microbes were obtained using iChips, and the extracts were screened for antibacterial activity. One bacterium, Eleftheria terrae, contacted a novel compound with antibacterial activity; the molecule was named teixobactin, and it appeared to have efficacy in the treatment of species of Enterococcus and Streptococcus. Teixobactin also had activity against Clostridium difficile, which is known to cause nosocomial diarrhea, and Bacillus anthracis, which has been used as an agent of bioterrorism [ 9 ]. Importantly, teixobactin demonstrated excellent bactericidal activity against S. aureus and was superior to vancomycin in killing late exponential phase populations and retained bactericidal activity against intermediate resistance S. aureus [ 2 ].

This finding has tremendous implications for patient care. S. aureus is a ubiquitous organism in the human population, and roughly one third of adults are asymptomatic carriers. However, the organism can cause deep-seated, life-threatening infection, including bacteremia, endocarditis, and end-organ disease [ 10 ]. Antibiotic-resistant strains of S. aureus, including vancomyin-intermediate S. aureus and MRSA, were once thought to be limited to specific settings, including healthcare facilities and gymnasiums, we know that this is now longer the case; community-acquired resistant strains appear all over the world [ 11 , 12 ]. These cases present a challenge as there are limited therapeutic options available to treat this potentially-lethal pathogen, and novel treatment options are urgently needed. The discovery of teixobactin was hailed as step forward in the quest to identify new treatment options, but less is known about how this compound and its analogs have advanced through preclinical testing.

3. Teixobactin analogs

Although the discovery of teixobactin was hailed as a leap forward for the development of novel antimicrobial agents, its development has been slowed due to technical hurdles [ 13 – 16 ]. The total synthesis of teixobactin is labor-intensive and low yielding (3.3%), and simplified versions of the compound were hypothesized to streamline production without compromising antimicrobial activity.

Shortly after the discovery of teixobactin, Parmar and colleagues reported the total syntheses and biological activities of two teixobactin analogs [ 17 ]. The approach held several advantages over existing methods: (1) it used commercially available building blocks, (2) employed a single purification step and (3) produced a good recovery (22%). The group established that the D-amino acids are critical for the antimicrobial activity of these analogs, setting stage for the development of additional analogs with antimicrobial activity [ 18 ]. Recent data indicates that macrocyclisation of teixobactin analogs with disulfide bridging is also important for antibacterial activity [ 19 ].

Teixobactin joins the list of other powerful non-ribosomal, D-amino acid antibiotics, including polymyxin and vancomycin. While early work suggested that teixobactin displayed high barriers to resistance, subsequent studies indicated that this might not prove to be accurate. For example, Li and colleagues recently described an early indicator of teixobactin resistance that was through genome-mining.

Subsequent work has yielded additional molecules that may serve as antimicrobial agents. These compounds are analogs of teixobactin that have been created to evaluate structure-activity relationship [ 20 ]. Parmar and colleagues have found success with this method by exchanging the l-allo-enduracididine with non-polar amino acids such as leucine and isoleucine that retain antibacterial activity against a variety of Gram positive pathogens, including MRSA [ 4 ].

While investigators continue to explore the antibacterial properties of teixobactin, others are attempting to fully elucidate its mechanism. One group has proposed that bactericidal effect of the molecule is due to its ability to arrest cell wall synthesis by blocking the formation of peptidoglycan [ 21 ]. This distinguishes it from other commonly used antibiotics that are used to treat Gram positive pathogens and may create a higher barrier to antimicrobial resistance.

Much has been written about the discovery of teixobactin and its analogs to potentially treat MRSA; however, comparatively little attention has been paid to the exorbitance expense associated with bringing such an agent to market. A phase 2 trial can cost more than $10,000,000 and a pivotal phase 3 trial might cost five times that amount [ 22 ]. As an infectious diseases clinical investigator, I am increasingly forced to confront the market forces that may limit the use of even the most promising antimicrobial agents.

For example, I am currently conducting a clinical trial with a new antimicrobial agent with activity against MRSA in the treatment of bacterial skin and soft tissue infections. This new agent is expensive – in excess of $4,000 per dose, and it is unclear if our hospital can justify the expense. (My trial is a pharmacoeconomic study to determine how best to utilize this compound). There are a number of existing agents on the market to address MRSA as well as VISA, including daptomycin, linezolid, doxycycline, clindamycin, and ceftaroline. Any new compound, even a promising new drug such as teixobactin, must compete in a crowded market and should demonstrate something novel to justify its expense. Inexpensive intravenous and oral options exist, and there is a burgeoning market for injectable agents such as dalbavancin, which has a long half-life and may be used in a single dose. Some new MRSA drugs cost several thousand dollars per dose, and hospital formulary committees are hesitant to add something so expensive to a hospital pharmacy’s budget.

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By contrast, there is far greater interest in the development of new agents to treat resistant Gram-negative infections, including carbapenemase-resistant Enterobacteriaciae such as Klebsiella pneumoniae carbapenemase. Several high-profile trials have demonstrated the utility of new agents to treat this infection, but similar studies addressing MRSA infections are lacking [ 23 ].

The situation with teixobactin is similar to what we have seen with another novel compound, malacidin, although the former is further along in development [ 24 ]. Using a sequence-guided screen of diverse soils for biosynthetic gene clusters, Brady and colleagues identified calcium-binding motifs that were later used to isolate malacidin, a new antimicrobial agent with activity against a variety of Gram positive organisms, including MRSA. Malacidin showed promise in the treatment of skin infections in an animal model, but it has not yet moved toward testing in humans. As with teixobactin, the reason for the delay appears to be due to both technical hurdles – both compounds are difficult to mass-produce – as well as challenges associated with investment. Thus far, neither compound has received robust funding necessary to progress through the regulatory hurdles associated with FDA approval.

Malacidin was identified through a culture-independent discovery platform that involves sequencing, bioinformatic analysis and heterologous expression of biosynthetic gene clusters captured on DNA extracted from environmental samples and could be used to identify more antimicrobial agents. However, it is unclear how these new products might fit into a crowded marketplace.

In addition to safety and efficacy studies, investigators should explore pharmaco-economic studies to identify the real-world costs and benefits associated with a new antimicrobial agent. This subdiscipline of health economics will undoubtedly play a larger role in the years ahead, as hospital formulary committees try to determine what antibiotics to carry. Some investigators are designing pharmaco-economic studies that focus on hospital length-of-stay to assess how a new agent affects patient care and hospital finances.

The cost associated with the preclinical and clinical development of a novel compound can easily exceed one billion dollars. While the discovery of teixobactin is exciting, and serves as an important proof-of-principal for newer agents, the case must be made that it (or its analogs) warrants further investment. Over the next 5 years, there will be tremendous interest in the development of teixobactin and its derivatives.

To that end, new work suggests that these derivatives may hold more promise than was once suspected. Ramchuran and colleagues have showed that three teixobactin derivatives have activity against MRSA and at higher concentrations, these compounds have activity against Gram negative organisms [ 25 ]. Unlike vancomycin, these derivatives showed early stage killing kinetics and comparatively little toxicity. Over the next few years, I anticipate a flurry of activity with these molecules as investigators try to determine if they might serve as a viable option for in vivo studies of Gram negative pathogens.

By replacing the Ile 11 residue with aliphatic isosteres, Ng and colleagues have generated derivatives of teixobactin that have activity against the Gram negative pathogen Pseudomonas aeuroginosa [ 26 ]. The rational design and synthesis of modified teixobactin analogs will undoubtedly lead to even more novel compounds and the next few years will be a crucial time to determine the most promising molecules.

Those of us on the front lines of healthcare are routinely reminded of the limitations of existing therapy – many patients had adverse reactions or are otherwise intolerant of currently-approved drugs – but this is not always clear to those who invest in antimicrobial agents. I routinely care for patients with multiple drug allergies who receive substandard care because there are not a sufficient number of alternatives. It is incumbent upon investigators, clinicians, and researchers to make the case for the development of new agents to address the expanding problem of antimicrobial resistance.

Declaration of interest

M W McCarthy has served as a paid consultant to Allergen. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

References

Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.

Wright G. Antibiotics: an irresistible newcomer . Nature. 2015 ;517(7535): 442 – 444 . [Crossref], [PubMed] , [Google Scholar]

•• An excellent overview of the discovery of teixobactin.

•• An important look at how derivatives of teixobactin are generated.

•• An excellent overview of MRSA epidemiology.

• An interesting look at various techniques for chemical synthesis.

• An interesting overview of teixobactin analogues.

Teixobactin: A Powerful Tool for Combating Resistant Strains

Tejal Rawal * and Shital Butani

Department of Pharmaceutics, Institute of Pharmacy, Nirma University, Ahmedabad-382 481, India

Date of Submission 02 July 2016
Date of Revision 17 October 2016
Date of Acceptance 15 November 2016
Indian J Pharm Sci 2016;78(6): 697-700

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms

DOI: 10.4172/pharmaceutical-sciences.1000172

Abstract

Resistance to antibiotics has grown out to be serious health dilemma. Despite this serious health crisis, no new antibiotics have been revealed since last 30 y. A new ray of hope in the form of teixobactin has come out of the dark which can prove to be effective in defeating resistance. This new antibiotic has an interesting mechanism of action against bacteria. The discovery of this wonderful compound has evolved as major breakthrough especially in this era of antibiotic catastrophe. This review article highlights various facets of teixobactin. Its chemistry, mode of action, in vitro and in vivo aspects have been thrown light upon in this review. Though the compound has not undergone clinical trial studies but its effect in mice models has given a hope for overpowering resistance. This article has been mainly communicated with an objective to provide information about teixobactin which has emerged as ray of hope for fighting antibiotic resistance.

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Keywords

Teixobactin, antibiotic, Eleftheria terrae, iChip, resistance, antimicrobial

A new crisis the world facing today is antibiotic resistance. Genetic modifications in bacteria have led to a condition, where pathogenic microorganisms have become more virulent and resistant to the available antimicrobial agents. The risk of resistance has also been accelerated due to overuse of the antibiotics. The most common example of overuse is by the people suffering from common cold and cough using antibiotics contributing to the development of antimicrobial resistance [1-6].

In recent years, pharmaceutical companies have reduced research efforts to develop new antibiotics. During 1980s, a new antibiotic teixobactin was discovered, which has potential to overpower many bacteria. Though this antibiotic might not be effective against some highly dreadful bugs, but it has the potential to make a huge influence on public health. However, this antibiotic still needs to undergo clinical trials. An important point to be considered in case of teixobactin is that it is active only against Grampositive bacteria. Teixobactin has not been reported to be effective in Gram-negative bacteria. The major reason for this might be the presence of an extracellular membrane in Gram-negative bacteria which protects them from several chemicals [7-14].

In the past, the well-known antibiotic, penicillin, which gained the title of ‘remarkable drug’ as well as referred to as «magic bullet» by Paul Ehlrich, gained these recognitions since it was highly effective against bacteria, without causing any harm to the body. It was found to be effective against organisms, where sulphonamides failed. Alexander Fleming who discovered penicillin warned about the development of resistance to the super drug. Later on, several resistant strains were unearthed. Fleming’s words served as an alarm to the world about the fact that the main cause of antibiotic resistance is the misuse of these drugs. Though the discovery of penicillin paved the path to discover more and more antibiotics, but resistance remained as a major challenge. This menace is driving the scientists to explore newer antibiotics, which can combat the resistant strains. In this struggle, teixobactin has evolved as a ray of hope for dealing with resistant bacteria [15].

There exists a desperate need for new antibiotics since the resistant strains have evolved as the major cause of suffering. Since long, no new antibiotic has been uncovered making the antimicrobial resistance a major concern. This alarming situation has raised the call for newer options in antibiotics. Scientists are struggling to discover new antibiotics since many years for countering the antibiotic resistance. One approach which has proved to be fruitful since many years is the discovery of new molecules through soil bacteria. After so many attempts, finally the scientists have succeeded in isolating an antibiotic, which exhibited potential against resistant strains and this antibiotic is teixobactin [16-21].

Teixobactin is basically a macrocyclic depsipeptide, which consist of 4 D-amino acids, methylphenylalanine and enduracididine [20]. It is composed of 11 amino acid chain, which is linked by about 10 peptide linkages. The last four linkages form a square shape. It consists of following amino acids, alanine, threonine, enduracididine, 4-isoleucine moieties, D-glutamine, 2 L-serine moieties and N-methyl-D-phenylalanine [22].

Many antibiotics have come out of the loam. For example, penicillin was obtained from a soil fungus named Penicillium and vancomycin also came from the soil bacteria. Similarly, teixobactin comes from a soil microbe named Eleftheria terrae. A device called iChip (a device consisting of specially designed 96 chambers, each surrounded by a semipermeable membrane) had been used by scientists in which the soil samples diluted with agar was placed. Then the iChip was immersed in the soil which allowed bacterial growth due to diffusion of numerous growth factors and nutrients (Figure 1). This method can be used in future for the development of several more potent antibiotics. After screening 10 000 strains of bacteria, 25 potential compounds were selected of which one is teixobactin with potent activity against Gram-positive bacteria [23-26].

Figure 1: Discovery of teixobactin using iChip.

Teixobactin acts by interfering with the synthesis of cell wall due to its ability to bind to two lipids, lipid II, which is a peptidoglycan precursor and lipid III, which is a teichoic acid (component of Gram-positive bacterial cell wall) precursor (Figure 2). It mainly attacks cell wall instead of targeting proteins. So basically, teixobactin can be considered as an inhibitor of peptidoglycan synthesis with practically no effect on the proteins, DNA or RNA. During the past 3 decades, it is the first new potent antibiotic reported. In mice models, it has shown potent activity against several resistant bacterial strains such as of Streptococcus pneumonia and Mycobacterium tuberculosis. It was also found to be active against methicillin-resistant S. aureus infections. It prevented the build-up of outer coats of the bacteria [20,21,26]. It appeared to have effect against some drug-resistant bacterial strains for example, methicillin-resistant S. aureus (MRSA) and vancomycin-resistant enterococci (VRE). It can also kill Clostridium difficile, M. tuberculosis and has the potential to be used as a treatment for tuberculosis (Table 1) [22,27,28].

Figure 2: Mode of action of teixobactin on lipids.

Drug Microorganisms Class of bacteria Activity
Methicillin S. aureus Gram-positive Development of resistance
Vancomycin Enterococci Gram-positive Development of resistance
Rifampicin M. tuberculosis Gram-positive Development of resistance
Teixobactin S. aureus Gram-positive No resistant strains found
Enterococci Gram-positive No resistant strains found
M. tuberculosis Gram-positive No resistant strains found
B. anthrasis Gram-positive No resistant strains found
All Gram-negative bacteria Development of resistance

Table 1: Antibiotic Activity Against Different Microorganisms

Teixobactin basically contains two massive nonribosomal peptide synthetase (NRPS)-coding genes named txo1 and txo2. When the sequencing of genome of E. terrae was done, it was found on the basis of 16S rDNA and in silico hybridization of deoxyribonucleic acid that the microorganism belongs to aqua bacteria group (Gram-negative group). A compound with 1242 Da molecular mass was isolated and was studied by mass spectrometry. Further, the compound’s stereochemistry was explored using nuclear magnetic resonance (NMR) and a homology search was performed to identify the gene cluster. The compound identified was named as teixobactin [21,22].

Teixobactin has shown remarkable activity against several infections and is under preclinical development. Researchers at the North Eastern University, Antimicrobial Discovery Centre reported that mice administered with teixobactin survived and did not show any sign of toxicity even after fatal doses of S. pneumoniae or MRSA. This prompted the scientists to progress this drug further to preclinical trials. If teixobactin becomes a success in the market, it will prove to be the first novel class of antibiotic in itself [28].

In in vitro experiments, teixobactin was found to be effective in retarding the growth of several Grampositive bacterial strains along with many drug resistant strains. When S. aureus was cultured with low teixobactin levels, no resistance was found to be developed in bacteria. In mouse models, the protective dose for teixobactin and vancomycin were found to be 0.2 mg/kg and 2.75 mg/kg for MRSA septicaemia, respectively. The protective dose here refers to the dose of the drug at which half of the animals survived. Thus, we can say that teixobactin is more potent than vancomycin. Reduction with teixobactin in bacterial levels was found to be 26 h post MRSA infection and 48 h post S. pneumoniae infection.

Ling et al. has shown in their studies that teixobactin was highly effective against Bacillus anthracis and C. difficile with minimum inhibitory concentration (MIC) of 5 and 20 mg/ml. No resistance was found in case of M. tuberculosis or S. aureus when plating with low dose of teixobactin (4×MIC) was done. In their studies, they found that teixobactin mainly inhibited peptidoglycan synthesis but has shown no effect on DNA, proteins or RNA thus giving the clue that protein is not its target.

Ling et al. performed in vivo studies in mice models. In serum, the potency of the compound was maintained. As per their studies, the pharmacokinetic parameters were found to be suitable after single injection IV dose of 20 mg/kg as the serum level was retained above MIC for about 4 h. In mice septicemia model, the mice infected with MRSA when treated with teixobactin intravenously, were found live. S. pneumoniae infected mice also showed a reduction of 6 log10 of colony forming units (CFU) in lungs with teixobactin [21,22].

Vancomycin is a glycopeptide antibiotic. Though vancomycin is a pretty effective antibiotic yet many bacteria like S. aureus have been found to develop resistance. Here comes an important role of teixobactin, which has been found to be active against VRE, and modifications in lipid II. The resistant strain had lipid II-D-Ala-D-Lac in place of lipid II-D-Ala-D-Ala arrangement. Teixobactin exhibited an ability to bind to this altered form of lipid II and render it inactive. Due to this amazing feature, teixobactin appeared to have the potential to be effective in infections caused by vancomycin resistant strains [21].

Numerous acyl depsipeptide antibiotics have emerged as a potent class, which in future is likely to play a key role in combating resistance to antibiotics. Examples are enopeptin A, enopeptin B, A54556A and B545556B. These depsipeptides mainly function by activating protease complex in bacteria which leads to degradation of uncontrolled protease which further hinders the cell division ultimately leading to cell death. The mechanism is based on the fact that the acyl depsipeptides cause degradation of protein FtsZ, which played a crucial role in cell division. This protein degradation further leads to failure of Z-ring formation [29].

Enopeptins A and B are acyl depsipeptides, which have been isolated from Streptomyces species RK-1051 from soil sample. These have been found to show high activity against S. aureus with a MIC of 12.5 μg/ml. Its activity against Gram-negative mutants has also been unveiled. The structure of enopeptin consisted of z lactone nucleus made up of amino acids and side chain of phenylalanine [30]. These have been isolated from a mixture of depsipetide factors from A-H (8 factors) and have been originated from S. hawaiiensis. They interfere with normal bacterial cell division which serves as their main mode of action [31].

Since last 30 years, no new antibiotic class has been identified in spite of an urgent requirement for a suitable antibiotic to counter antimicrobial resistance. Teixobactin turned out to be the first new class of antibiotics with considerable activity against resistant strains. This antibiotic has the potential to be a powerful tool to combat resistance microorganisms as has it exhibited excellent activity in mice models.

Teixobactin

a Department of Chemistry, University of Warwick, Coventry, UK
E-mail: j.r.lewandowski@warwick.ac.uk

b School of Life Sciences, University of Warwick, Coventry, UK

c NovoBiotic Pharmaceuticals, Cambridge, USA

d Univ. Grenoble Alpes, CNRS, CEA, IBS, F-38000 Grenoble, France

e Antimicrobial Discovery Center, Northeastern University, Department of Biology, Boston, MA 02115, USA

Abstract

Teixobactin is a new promising antibiotic that targets cell wall biosynthesis by binding to lipid II and has no detectable resistance thanks to its unique but yet not fully understood mechanism of operation. To aid in the structure-based design of teixobactin analogues with improved pharmacological properties, we present a 3D structure of native teixobactin in membrane mimetics and characterise its binding to lipid II through a combination of solution NMR and fast (90 kHz) magic angle spinning solid state NMR. In NMR titrations, we observe a pattern strongly suggesting interactions between the backbone of the C-terminal “cage” and the pyrophosphate moiety in lipid II. We find that the N-terminal part of teixobactin does not only act as a membrane anchor, as previously thought, but is actively involved in binding. Moreover, teixobactin forms a well-structured and specific complex with lipid II, where the N-terminal part of teixobactin assumes a β conformation that is highly prone to aggregation, which likely contributes to the antibiotic’s high bactericidal efficiency. Overall, our study provides several new clues to teixobactin’s modes of action.

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