Imogen Ramsden: A bio-informatics approach to identify new drug targets in multidrug-resistant bacteria

In 2019,19 Antimicrobial Resistance Collaborators found that drug-resistance infections killed at least 1.27 20 million people worldwide, and nearly 5 million deaths associated with bacterial antimicrobial resistance (AMR). 21 1 With predictions raising the number of deaths due to bacterial AMR to 10 million deaths annually by 2050, 2 22 the UN Environment Programme, the US Centers for Disease 23 Control and Prevention (CDC), World Health Organisation (WHO) and European Commission have recognised the need for urgent global action.3-7

The cost of antibiotic research and low rate of novel antibiotic translation chiefly due to the 26 extremely unfavourable cost-benefit ratio, has discouraged big pharmaceutical companies from developing new antibiotics.8-10 27 Consequently, only 17 new antibiotics have been approved between 2010 and 2021, 1, 11 28 five of which are not in circulation due to the companies’ finances.8, 9 29 Only four of these new antibiotics represent new classes of antibiotics, targeting bacteria through novel mechanisms.12, 13 30 Though there have been three new FDA-approved 31 antibiotics last year (2024), experts worry that this could be a peak due to their associated scientific, regulatory and financial challenges. 14 32 It remains that many of the broad-spectrum 33 antibiotics currently in use are not effective against multidrug-resistant bacteria, thus it is critical to look for novel drug targets specific to these species. In 2017, the WHO published a priority pathogens list for research and development of new antibiotics5 , updated in 2024, 15 35 36 and dominated by Gram-negative bacteria. 

This list was composed of multidrug-resistant bacteria – against some of which even the last-resort antibiotic colistin is ineffective.16, 17 37 This 38 list was used as the starting point of this investigation which endeavours to identify new drug 39 targets to combat multidrug-resistant bacterial infections. 40 Membrane proteins constitute the largest class of drug targets as they are responsible for vital 41 physiological processes such as nutrient and waste transportation, signal transduction, and enzymatic catalysis.18, 19 42 Due to their placement in the membrane, membrane proteins fold in 43 a very specific way so that the hydrophobic residues are buried in the hydrophobic membrane 44 core, while the more polar residues tend to reside either side of the membrane where they are exposed to aqueous environments. 

45 20 Membrane proteins divide overwhelmingly into two 46 major structural classes, which reflects the two secondary structural motifs that are stable in lipid bilayer membranes: the alpha (α)-helix and the beta (β)-barrel.21, 22 47 α-helical proteins are 48 found in the inner membranes of Gram-negative bacteria, Gram-positive bacteria, and 49 eukaryotes while β-barrel proteins are almost exclusively found in the outer membranes of Gram-negative bacteria.23-25 50 In an effort to identify a new target for broad-spectrum antibiotics 51 this investigation will focus on α-helical transmembrane proteins.

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