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New generation efflux-resistant antibiotics

PI name:  

Dr K Miraz Rahman

Portfolio Manager:

Dr Barry Porter

Background:  

Antibiotic project mascotThe discovery of antibiotics in the early 20th Century had a dramatic impact on healthcare, leading to the effective treatment of previously deadly infections such as pneumonia, a marked reduction in the risks of surgery and childbirth and enabled advanced interventional medicine, which many now consider as routine.  

However, antimicrobial drug resistance is a growing threat to global public health.  Multidrug resistance among the ‘ESKAPEE’ organisms is of particular concern as they are responsible for many of the serious hospital infections.

Despite the recognised need for new antimicrobials for clinical use, only two new classes of antibiotics have been brought to market in the last 50 years and many major pharmaceutical companies have now left the field.   

Technology Overview:

As removal of the drug from the bacterial cell by efflux pumps plays a key role in resistance to most antibiotics, it is not surprising that a considerable amount of effort has gone into the development of discrete agents that block the efflux pumps and can be co-administered with an antibiotic.  However, this approach has proved ineffective as the antibiotic still competes for binding at the pump and is thus equally likely to be eliminated.

The function of efflux pumps in development of bacterial resistance
Fig1. - The function of efflux pumps in development of bacterial resistance

The King’s College London and Public Health England teams have circumvented this problem by incorporating antibiotic activity and efflux pump inhibition within the same molecule using a patented technology platform allowing the antibiotic to effectively block its own efflux.

Proprietary technology combining antibiotic activity as well as efflux pump inhibition
Fig2. - Proprietary technology combining antibiotic activity as well as efflux pump inhibition

As a first approach, the team have focussed on the hugely commercially successful fluoroquinolone series of antibiotics and after applying our technology, have developed potent novel fluoroquinolone antibiotics with broad spectrum activity that also effectively block efflux and show a low probability of developing resistance.  These compounds show a good oral pharmacokinetic profile and are orally active in the standard thigh infection model.

Further profiling of these compounds is underway along with work in parallel to extend their spectrum of activity.

Applications and Benefits: Potential use cases and/or markets. The advantages over existing solutions (eg, faster, more accurate).

Fluoroquinolone antibiotics have been at the forefront of fighting infectious diseases for half a century but with resistance to this class of antibiotics rising, alternatives are urgently required.  Although new antibiotics are welcome, it is desirable that these new agents also incorporate some form of mechanism to combat resistance in order to break or even delay the emergence of resistance giving the drug a longer useful working life.

Opportunity:

An overview of the opportunities you're searching for. (e.g. Available for exclusive and non-exclusive licensing / seeking co-development partners etc.)

The Project is currently seeking licensees or partners to fund and support development of the novel fluoroquinolone series through candidate selection and workup to IND.

We are also considering seeking investment to create a platform company that could exploit multiple antibiotic targets incorporating our proprietary efflux-resistant technology.

Further Details:  

PCT/GB2018/051468 Claiming Priority to GB Patent Application No. 1708606.7  Antibiotic Resistance Breakers

An overview of bacterial efflux pumps and computational approaches to study efflux pump inhibitors; Future medicinal chemistry 8(2) January 2016

Role of bacterial efflux pumps in biofilm formation; Journal of Antimicrobial Chemotherapy. 73, 8, p. 2003-2020

Mapping the Dynamic Functions and Structural Features of AcrB Efflux Pump Transporter Using Accelerated Molecular Dynamics Simulations:  Jamshidi, S., Sutton, J. M. & Rahman, K. M. 11 Jul 2018 In : Scientific Reports. 8, 1, p. 1-13 , 10470

Computational Study Reveals the Molecular Mechanism of the Interaction between the Efflux Inhibitor PAβN and the AdeB Transporter from Acinetobacter baumannii:  Jamshidi, S., Sutton, J. M. & Rahman, K. M. 28 Jun 2017 In : ACS Omega. 2, 6, p. 3002-3016

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