Antibiotics are an essential pillar of modern medicine. However, after almost 90 years of deployment in the fight against bacterial pathogens, we are now being brought to the mercy of microbial resistance. “Global crisis,” “return to medical dark ages,” “antibiotic apocalypse” are some of the terms being used by prominent scientists, physicians, and politicians to depict the future of medicines for bacterial infections. But, in an age of rapid innovation, are we defeated by our microbial adversaries? Or, is there a silver bullet in the pipeline – a super drug to beat the superbugs?

The Problem

The short life cycles of bacteria make them very good at evolving to adapt to their environment. Escherichia coli, for instance, has a doubling time of about 20 minutes. This means that within 7 hours, 21 generations are obtained. So, a single cell can produce a population of 2 million bacteria within a few hours. When placed in a medium containing antibiotics designed to kill the microbes, they rapidly develop or acquire resistance mechanisms to circumvent this threat. Known resistance mechanisms include efflux pumps, degradation enzymes and target modification enzymes. If even one of the 2 million bacteria develop resistance, it is only another 7 hours (or 21 generations later) until the population is back up to 2 million. Hence, in this new colony of resistant bacteria, the antibiotic will no longer be effective.

Counteracting Resistance Mechanisms

Inhibitors that target resistance pathways represent a promising new frontier. One such inhibitor is avibactam, a first-in-class compound which targets beta-lactamase. It is formulated with Ceftazidime, a broad spectrum, penicillin-like, beta-lactam antibiotic. Ceftazidime kills the microbe, while avibactam disarms the bacterial resistance mechanism, preventing degradation of the antibiotic.

Currently, the drug has been approved for intravenous administration to treat a number of increasingly ‘untreatable’ infections including complicated intra-abdominal infections (cIAI), complicated urinary tract infections (cUTI) and hospital-acquired pneumonia. Avycaz was launched in the U.S. in 2015 by Allergan, and Zavicefta is being rolled out in the rest of the world in 2017 and 2018 by Pfizer. The combination drug is also being tested in trials with Aztreonam, a monobactam antibiotic, effective against metallo-beta lactamase.

Further down the pipeline, Bioversys is developing their capability to screen, identify and develop Transcriptional Regulator Inhibitory Compounds (TRICs). TRICs target resistance mechanisms via the transcriptional apparatus of the bacterial cell. Their lead TRIC compound has been successfully tested with ethionamide, one of the WHO’s ‘Essential Medicines’, against multi-drug resistant Mycobacterium tuberculosis. Bioversys is now collaborating with Aptuit, a drug discovery and development specialist, to identify novel approaches to target gram-negative pathogens.

Boosting Defense Mechanisms

Another innovative strategy to fight bacterial pathogens is to improve the ability of the patient’s immune system to fight infections. Soligenix is developing a drug to do just this, called Dusquetide (SGX94). Dusquetide is a short, synthetic peptide belonging to a class of Innate Defense Regulators (IDRs). It works by improving how the body deals with infection. IDRs modulate the innate immune response to pathogen-associated and inflammatory signalling, thereby speeding up resolution of the infection and preventing tissue damage through harmful inflammation. Although it is not an antibiotic within itself, it may be used as a combination therapy to improve the action of existing antibiotics. As it modulates the host immune system rather than the microbe, there is minimal chance of antimicrobial resistance.

Dusquetide is currently being tested in an ongoing Phase II, dose-escalating clinical study of oral mucositis in head and neck cancer patients. Preliminary results demonstrated a 50% reduction in the median duration of severe oral mucositis in the Dusquetide group compared with placebo.

Drug Development Platforms

Beyond improving the efficacy of existing antibiotics, what can we do to develop new antibiotics?  Next generation sequencing, bioinformatics, and advanced analytics will be key tools for rational antibiotic design platforms.

Discuva, a UK-based drug discovery startup, focuses on developing new antibiotics against drug-resistant pathogens using their Selective Antibiotic Target IdentificatioN (SATIN) technology platform. SATIN identifies new molecular targets of chemical compounds to disrupt bacterial growth, viability and resistance mechanisms. High throughput next generation sequencing, advanced bioinformatics and machine learning are used to continuously analyze transposon libraries, allowing the researchers to track bacterial events throughout drug development. This facilitates the development of more targeted antibiotics for specific pathogens, which in turn, reduces the spread of antibiotic resistance. Their primary focus is currently on multi-drug resistant bacteria responsible for urinary and respiratory tract infections, sepsis and sexually-transmitted diseases. Discuva have an ongoing partnership with Roche, which was recently extended until 2018.

Beyond Pharmaceuticals

Photodynamic Therapy (PDT) uses light, in conjunction with ‘photosensitizer’ molecules, to produce reactive oxygen species (ROS). The ROS induce a broad spectrum but highly localized, cytotoxic effect. A recent study from Saarland University, Germany, tested the use of chlorin e6, a derivative of the plant pigment, chlorophyll, and red light against multi-drug resistant Pseudomonas aeruginosa. PDT was shown to be successful in killing the bacteria temporarily, however, the authors noted that there was bacterial regrowth after 48 hours. Further research will be required to determine the optimal concentrations of chlorin e6 as well as the number of treatments to produce a lasting effect.  

The key advantage of PDT is that the ROS-based mechanism is very general. ROS are an intrinsic component of cells, generated in metabolic processes, and have roles in intracellular signalling  pathways. Therefore, it is challenging for bacteria to develop resistance without impeding their own signalling pathways. The key disadvantage is the dependence of this treatment on light transmission into a tissue. Although red light is used, which has a deep penetration depth in human tissue, there may be some areas where PDT is less effective.

What Next?

The fight against multi-drug resistant bacteria is a double-pronged attack. Firstly, the resistance mechanism must be side-stepped, followed by killing the bug itself. Combination therapies represent a new hope for boosting the effectiveness of existing antibiotics. But, how long will it be until the microbes develop or acquire new pathways of resistance? A longer term solution may lie with completely new targets. The problem with searching nature for a wonder drug, is that it is difficult to find toxins that bacteria haven’t already evolved defenses for. This is particularly true when it comes to antibiotics, which are already the ‘weapons-of-choice’ within microbial communities. The greatest chance of success is likely to lie in identifying completely new targets and mechanisms, for which no natural antibiotics currently exist.

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