Antimicrobial Resistance

The world is running out of antimicrobials.

Antimicrobial resistance (AMR) is one of the most serious global healthcare threats.

Increasing numbers of bacteria are resistant to the action of currently available antimicrobials.

New antimicrobials brought to market over the past 30 years have been derivatives of existing class of antibiotic originally discovered between the early 1900s and 1984. The discovery and development of new antimicrobials has slowed dramatically over the last 30 years as less-attractive returns on investment and challenging science led to a number of drug companies abandoning their antibiotic research.

Antibiotic stewardship will help slow the spread of AMR, it cannot halt it and existing antimicrobials will continue to lose their effectiveness over time. As a consequence, patients will continue to need new antimicrobials and treatment options to combat the ever growing threat of AMR

Key bacterial pathogens

The ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) are responsible for a significant proportion of nosocomial infections throughout the world. They represent the vast majority of clinical isolates whose resistance to multiple antimicrobials presents major challenges for effective therapeutic intervention by clinicians.

Of particular note are the Carbapenem-resistant Enterobacteriaceae (CRE), a sub-group of Gram-negative bacteria e.g. Escherichia coli and Klebsiella species which are resistant to the carbapenem class of antimicrobials . This class of antimicrobials is typically reserved for the treatment of more serious clinical infections. CRE are often considered as the new “superbug” as these bacteria can kill up to half of the patients who develop bloodstream infections from these pathogens.

Worryingly, carbapenem resistance is growing exponentially – resistant Klebsiella rose from 0.6% to 5.4% between 2004 and 2008 in the US, and in Thailand 70% of Pseudomonas infections are carbapenem resistant.

Why do we need a new class of antimicrobial?

Antimicrobials can be categorised based on similarities in their chemical structure e.g. the β-lactam or the quinolone classes of antimicrobials. Given the common structural feature(s) within a class, resistance to one antibiotic can therefore result in resistance to multiple members of the same class. Consequently, there is a need to develop novel, structurally distinct classes of antimicrobials that will not be susceptible to the resistance mechanisms bacteria have developed against current classes of antimicrobials.

Why are there so few antimicrobials to treat gram-negative bacteria?

Bacteria have evolved mechanisms to prevent the entry of unwanted toxic compounds such as antimicrobials into their cells.

Gram-positive bacteria have only a single cell membrane which is relatively easy to cross so many types of antimicrobials can achieve entry into the cell.

Gram-negative bacteria have a double cell membrane and a number of efflux pumps which can expel toxic compounds out of the cell therefore making it more challenging to design new antimicrobials that can enter the cell and kill these bacteria.

Barriers into Antibiotic Entry Into Gram-Negative Bacteria

barriers

Diagram source: A report from The Pew Charitable Trusts:  A scientific roadmap for antibiotic discovery. 2016