Therapeutics


major economies, to commit investment in research, innovation and development of innova- tive health technologies to counter threats from antimicrobial resistance. To better diagnose the problem, the US National Institutes of Health (NIH) completed the first phase of its Antimicrobial Resistance Diagnostic Challenge, a federal competition that will award up to $20 million in prizes for the development of rapid, point-of-need diagnostic tests to combat drug-resistant bacteria. Ten semi- finalist were selected and each received $50,000 to develop their concepts into prototypes. While policy initiatives and government funding are a major step forward, they will not be sufficient to solve this problem. In its Scientific Roadmap for Antibiotic Discovery, The Pew Charitable Trusts concluded that the biggest barriers to finding new classes of antibiotics are not regulatory or finan- cial: they are scientific.


New science needed


There has not been a novel antibiotic class approved for use against Gram-negative infections in the last 40 years. However, the lack of novelty is by no means an indication of lack of effort devoted to this cause.


Across the public, private and academic industries DATE August 2016 EVENT


A Nevada woman died from a carbapenem-resistant Enterobacteriaceae infection resistant to 26 different antibiotics – essentially every antibiotic available to healthcare providers.


December 2016


The University of California Irvine Medical Center acknowledged that 10 infants contracted methicillin- resistant Staphylococcus aureus (MRSA) in its neonatal intensive care unit. Two months earlier, the World Health Organization had declared MRSA to be in one of a dozen families of super bacteria that “pose the greatest threat to human health.”


April 2016


A Pennsylvania woman was found to be carrying a strain of E. coli resistant to colistin, an antibiotic of “last resort”, heralding the “emergence of a truly pan-drug resistant bacteria”, according to the doctors who discovered it.


2005-2016


Between 2005 and 2016, multidrug-resistant gram negative bacteria (MDR-GNB), such as Escherichia coli, were found in more than a quarter of nursing home residents on average, according to a meta-analysis published in the American Journal of Infection Control.


Table 1: Antibiotic-resistant bacteria in the news 10


many extensive drug discovery endeavours have been undertaken, only to come up short of a novel thera- peutic. The reason for these numerous failures lies in the inability to get good inhibitors to their targets in Gram-negative bacteria. The structure of a bacte- ria’s cell wall determines whether it is Gram-positive or Gram-negative (Figure 1). The Gram-positive cell wall consists of a thick peptidoglycan layer and a phospholipid membrane, while Gram-negative bac- teria possess an inner membrane consisting of phos- pholipid, a thin peptidoglycan layer, plus an outer membrane. The outer membrane of Gram-negative bacteria is an asymmetric bilayer composed of glyc- erol phospholipids and lipopolysaccharide (LPS). LPS acts as a barrier against toxic compounds, including antibiotics, whose targets typically reside within the inner membrane. It is not surprising that Gram-negative bacteria cause a wide spectrum of diseases, including urinary tract, bloodstream, air- way, venereal and healthcare-associated infections. Both CDC and WHO have singled out Gram-nega- tive bacteria for special attention, as most antibiotics work well against Gram-positive bacteria, but not Gram-negative.


In a 2016 study update, the Pew Charitable


Trusts surveyed antibiotics currently in clinical development and made a disheartening prediction: of the dozens of antibiotics in clinical development, only one in five are expected to be approved for use. Despite the seeming doom and gloom, a num- ber of novel strategies have begun to emerge for combating antibiotic resistant bacteria, especially for those of the Gram-negative type. The approach- es can be grouped into a number of categories including activating existing antibiotics, indirect therapeutics, biologics and small molecules.


Activating existing antibiotics


Gram-negative bacteria have a protective outer barrier and fewer internal defences common among the Gram-positive bacteria, such as enzymes that degrade antibiotics or mechanisms that pump antibiotics back out of the cell (efflux). Breeching the outer barrier makes Gram-negatives vulnerable to a wide range of existing antibiotics. A company in the US, Spero Therapeutics, is developing a series of novel chemical entities – Potentiators – that specifically interact with the outer membrane of Gram-negative bacteria to dis- rupt and increase the membrane’s permeability (Figure 2). This increase in permeability allows both novel and existing Gram-positive antibiotics to enter and kill the cell.


The first Potentiator candidate, SPR741, a derivative of polymyxin B currently being evaluated


Drug Discovery World Summer 2017


Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68  |  Page 69  |  Page 70  |  Page 71  |  Page 72