Teixobactin: a novel anti-infective agent

KEYWORDS:

• Antimicrobial
• iChip
• chemical synthesis
• analogs
• teichoic acid

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.

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 Ile¹¹ 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.

Additional information

Funding

The manuscript was not funded.