Antibiotics against drug-resistant infections are now regarded as a significant and very urgent area of unmet medical need, yet many big pharma companies show little interest in developing new antibiotics. Dr Sarah Houlton reviews the situation and looks at recent progress
The growing prevalence of bacteria that are resistant to some, most, or even all, antibiotics poses a significant threat to human health. The introduction of penicillin in the 1940s, and numerous antibiotics that followed it, have had a dramatic impact on public health. Many bacterial infections that had high mortality and morbidity rates became routinely curable. Now, the emergence of untreatable infections is changing this. In the US, according to the Centers for Disease Control and Prevention (CDC), an estimated two million people become infected by a resistant bacterium of some form, and at least 23,000 of these will die as a direct result of the infection.
CDC gives the highest rating, of ‘urgent threat’, to three bacteria: Clostridium difficile, carbapenem-resistant enterobacteriaceae, and Neisseria gonorrhoeae. C. difficile is by far the biggest killer – with almost half a million infections and 15,000 deaths directly attributable to the infection per annum, resulting in US$1bn in excess medical costs every year. Of these, more than 100,000 of those infected were nursing home residents, and at least 80% of the deaths were in those over 65. It is the most common microbial cause of healthcare-associated infections in US hospitals.
C difficile is the most common microbial cause of healthcare-associated infections in US hospitals
The incidence of the second on the danger list, carbapenem-resistant enterobacteriaceae, is also increasing in medical facilities, with strains of klebsiella and E. coli a particular problem. Of the 9,000 who contract one of these bacteria, 600 will die, and if it leads to sepsis, this will prove fatal in nearly half of all cases. These bacteria are resistant to almost all of the existing antibiotics.
The increasing rate of gonorrhoea infection is another big worry. Nearly a quarter of a million Americans will contract some form of drug-resistant Neisseria gonorrhoeae every year – that’s about a third of all cases of gonorrhoea. About three-quarters will be resistant to tetracycline, and sensitivity to cefixime, ceftriaxone and azithromycin are not uncommon. The growth in resistance to ceftriaxone is of particular concern, as this is the usual treatment of choice, with resistance to many of the other antibiotics already commonplace.
Although these three represent the biggest health threats, they are far from the only bacteria where resistance is an issue. Some are well known – methicillin resistant Staphylococcus aureus, vancomycin-resistant enterococcus, drug-resistant Streptococcus pneumoniae, multidrug-resistant Pseudomonas aeruginosa – but there are many others. As resistance rates rise, it would seem likely that some of these will move from ‘serious threat’ to ‘urgent threat’ status on CDC’s list.
The situation is no prettier in Europe. Yet, despite the fact that antibiotics represent a significant chunk of pharma revenues – the fifth largest therapeutic area by sales, with global sales of $40bn in 2014, according to IMS Health – there has been little incentive for big pharma companies to work in the area in recent years, although it is a significant unmet medical need. One reason is that any new antibiotic that has activity against resistant bacteria will not be put into routine use. Rather, it will be saved as a last line of defence against those resistant bacteria. While this is essential, it does somewhat limit its revenue raising potential. However, some big pharma companies are still active in the area, alongside numerous biotechs and academic groups.
As bacteria mutate to evade existing drugs’ mechanisms of action, those medicines that act via novel mechanisms are particularly important
As bacteria mutate to evade existing drugs’ mechanisms of action, those medicines that act via novel mechanisms are particularly important. Several first-in-class drugs have indeed reached the market in recent years, including daptomycin from Cubist (now Merck), which is a lipopeptide antibiotic that creates holes in the bacterial membrane by inserting itself into the membrane and altering its shape. Also relatively new is Pfizer’s linezolid, an oxazolidinone that affects the translation of mRNA into proteins in the ribosome, and fidaxomicin, acquired from Optimer by Cubist, which inhibits one of the subunits of RNA polymerase to affect protein synthesis.
Various other new targets are being investigated. For example, the bisphosphocin class of antibiotics being developed by Florida-based Lakewood Amedex, are broad spectrum antibiotics that disrupt the bacterial cell membrane in both Gram positive and Gram negative bacteria, including resistant organisms such as MRSA. They also have activity against fungal targets.
The sugar-based molecules contain two phosphate groups, each linked to a linear carbon chain, and have shown in vitro activity against more than 70 bacterial strains. Importantly, no resistant strains have been either found or created in these tests. The bisphosphocins bind to the cell membrane, thus disrupting it, causing it to become depolarised, and thus leading to cell death. The lead molecule, Nu-3, is being investigated in early stage clinical trials, initially in topical form for complicated diabetic food ulcers, and as a follow-on as a first-line systemic antibiotic to complicated urinary tract infections.
The broad spectrum antibiotic activity of vancomycin also disrupts the gut flora that, under normal circumstances in healthy individuals, keeps the growth of C. difficile under control
The lead product at Colorado-based Crestone, CRS3123, is in Phase I for the treatment of C. difficile infections. There are only two antibiotics licensed for the treatment of C. difficile infection, vancomycin and fidaxomicin. However, the broad spectrum antibiotic activity of vancomycin also disrupts the gut flora that, under normal circumstances in healthy individuals, keeps the growth of C. difficile under control, and recurrence rates in patients treated with vancomycin are at least 20%. The situation is not so bad with fidaxomicin under normal circumstances, but epidemic strains that have recently emerged have 20%-plus recurrence rates after treatment with either drug thanks to the formation and presence of spores.
CRS3123 is a small molecule inhibitor of protein synthesis that acts at the novel target methionyl tRNA synthetase, MetRS, which transfers methionine to its cognate tRNA during protein synthesis. The molecule has been shown to be highly potent in vitro against all clinical isolates of the bacteria that were tested. As it is a narrow spectrum antibiotic with a high degree of C. difficile specificity, this may assist in leaving gut flora undisturbed. It also inhibits the production of toxins by the bacteria, which may give reduced mortality and morbidity rates, and also inhibits the formation of spores, which should reduce transmission and recurrence rates.
C. difficile is also one of the bacteria being targeted by South San Francisco, CA-based AvidBiotics. Its technology has its roots in naturally occurring R-type bacteriocins. These bacterial proteins evolved to kill off specific strains of competing bacteria, and one protein is sufficient to kill an individual bacterium. The company’s technology platform is designed to engineer bacteriocins targeted at bacteria that pose a threat to human health.
These proteins, given the name Avidocins, bind to molecules that are unique to the surface of the target bacteria, and do not appear on the surface of other bacteria. This leaves other bacteria unharmed, particularly those that inhabit the gut and the vagina, which can all too often lead to unwanted side-effects such as gastrointestinal disturbances or fungal infections when their population is affected.
Avidocins are not acting via the mechanisms that lead to antibiotic resistance, and thus should remain effective against resistant strains
The company claims that they can be designed rapidly to kill almost any bacterium, whether Gram positive or Gram negative. Furthermore, they are not acting via the mechanisms that lead to antibiotic resistance, and thus should remain effective against resistant strains. As they are designed to target surface accessible virulence or fitness factors, should resistant bacteria develop, their virulence or fitness will be compromised.
Positive preclinical studies have been achieved in mice inoculated with C. difficile spores. They were treated orally with the appropriate Avidocin protein, and not only did they remain uninfected, but also no disturbances in their healthy gut bacteria could be detected. The company also developed C. difficile mutants that were resistant to Avidocin proteins, and the ability of these to spread and cause disease was compromised. It also believes that the proteins might be useful prophylactically in high risk patients.
Achaogen, also based in South San Francisco, is focusing on novel treatments for Gram negative bacteria. Its furthest advanced project, the antibiotic plazomicin, is in Phase II studies for the treatment of both complicated urinary tract infections (cUTIs), and Phase III for BSI and pneumonia. Here, the target bacteria are carbapenem resistant enterobacteriaceae, or CRE. It also has two programmes, involving LpxC inhibitors and an antibacterial antibody, targeted at P. aeruginosa and Acinetobacter baumannii, as well as other Gram negative programmes in earlier stages of development.
E.Coli is a particular problem in medical facilities
CRE include a number of related Gram negative bacteria, notably E. coli and Klebsiella pneumonia, and carbapenem antibiotics are one of the last lines of defence against these strains. Phase III trials of plazomicin began in late 2014, and it has been granted fast-track designation by the FDA for the treatment of serious and life-threatening CRE infections. The drug is an aminoglycoside that was designed to overcome the most clinically relevant resistance mechanisms. Aminoglycosides have been in use for the treatment of bacterial infections for more than half a century, but resistance is now common.
The starting point for plazomicin was the existing drug sisomicin, which was modified to overcome aminoglycoside resistance mechanisms. Plazomicin retains activity in strains where the potency of other antibiotics is now limited thanks to resistance. It has already been shown in a Phase II trial to have comparable efficacy to levofloxacin in patients with cUTIs caused by enterobacteriaceae.
Uncomplicated gonorrhoea is becoming increasingly difficult to treat as the bacterium has developed resistance to so many different existing antibiotics
In early 2015, AstraZeneca span out its antibacterial research into a new entity, Entasis Therapeutics, based in Waltham, near Boston, MA. Its furthest advanced product, now coded ETX0914, is in Phase II for the treatment of multidrug resistant Neisseria gonorrhoeae. It represents the first of a novel class of molecules for the treatment of uncomplicated gonorrhoea, an infection that is becoming increasingly difficult to treat as the bacterium has developed resistance to so many different existing antibiotics. It has been awarded FDA Fast Track status.
The company’s drug discovery platform is focused on serious Gram negative infections. In particular, it is looking at drugs to counteract bacteria such as Pseudomonas aeruginosa, Acinetobacter baumanii and CRE. It uses genetic tools, molecular dynamics simulations and modelling to direct its search for new actives.
Tetraphase Pharmaceuticals is also based in the Boston area, in Watertown. It is using chemistry technology spun out of Andrew Myers’ group at Harvard, and enhanced in house, to create novel tetracycline drugs. Tetracyclines have been used as antibacterial agents for more than 50 years, all of which are made semi-synthetically, using technology that is only capable of making limited modifications to their chemical diversity. The company’s technology uses a practical fully synthetic process to create novel tetracycline antibiotics, with a vastly wider array of derivatives possible – nearly 3,000 new tetracyclines have already been made in this way.
The furthest advanced product, eravacycline, has undergone Phase III trials for the treatment of complicated intra-abdominal infections (cIAIs) and complicated UTIs. Although it met the primary efficacy endpoint with favourable safety and tolerability in the cIAI trial, it did not in cUTIs. It is also in Phase I for the treatment of pneumonia. The fully synthetic tetracycline antibiotic has potent antibacterial activity against a broad spectrum of bacteria, both susceptible and multidrug-resistant, including Gram negative, Gram positive, atypical and anaerobic. It was shown to have activity in vitro against such MDR pathogens as A. baumannii and enterobacteriaceae, and has FDA fast track status.
Other products are in the earlier stages of development, including TP-271, which is in preclinical studies. It is hoped that it will be able to protect against certain biothreats agents, including Francisella tularensis, which causes tularemia, the pathogen that causes bubuonic plague, Yersinia pestis, and the anthrax-causing bacterium Bacillus anthracis. A second-generation Gram-negative antibiotic is also being pursued.
A second company, Macrolide Pharmaceuticals, has recently been spun out based on Myers’ chemistry, and is also based in Watertown, MA. In a much earlier stage of development, it builds on Myers’ total synthesis of macrolide antibiotics. Existing macrolides, such as azithromycin, erythromycin and clarithromycin, have been very successful, but bacterial resistance is causing problems, and the ability to make derivatives is limited. Myers’ chemistry facilitates the creation of novel macrolides that were previously impossible to make. More than 200 have already been made, and in vitro testing of these show that they may have potential as antibiotics.
In the US an estimated two million people become infected by a resistant bacterium of some form, and at least 23,000 of these will die as a direct result of the infection
A macrolide in the late stages of trials, solithromycin, is being developed by Cempra in Chapel Hill, NC. It represents the first fluoroketolide, and has broad spectrum activity against macrolide-resistant bacterial that is both orally and intravenously available. It has already completed a Phase III trial in patients with community-acquired bacterial pneumonia in oral form, and trials where it is administered intravenously are also underway in this indication. Orally dosed product is also in Phase III for uncomplicated gonorrhoea.
Antibodies too are being investigated as antibiotics
Antibodies too are being investigated as antibiotics, for example by California-based Trellis Bioscience. It uses proprietary CellSpot technology to screen antibodies for 10 different parameters at the same time, such as affinity, specificity and cross-reactivity with other antigens, screening up to a million healthy donor human blood cells in a few days. The company believes that this will assist them in the discovery of highly efficacious antibodies, which ought to be more resistant to emergent drug resistance.
Its furthest advanced antibody in the antibacterial field, TRL1068, is a clinical candidate designed to eliminate bacterial biofilm, the most common cause of clinically significant antibiotic failure. The antibody binds to a protein secreted by the bacteria that plays a crucial role in creating the biofilm scaffold. When this target protein was extracted with a high affinity monoclonal antibody against a site that is conserved across homologues from most bacterial species, the result was a dissolution of the biofilm in vitro. And in an infected implant mouse model, it reduced biofilm-associated bacteria by more than 99%. Importantly, the released bacteria regained their susceptibility to antibiotic treatment.
These represent just some of the many scientific strategies that are being used to bring new antibiotics to the market. While it is unlikely that all will succeed, the complexity and challenge presented by emerging pathogens that are resistant to multiple drugs and classes means that the more technologies that are developed, the more likely it is that those much-needed new drugs will become available.