Current Antibiotic Pipeline

Endogenous mechanisms of resistance

Single mutation reducing target affinity

Multistep mutations reducing affinity/remodelling target

General efflux mechanisms

Reduced uptake

Loss of activation

Upregulation of target

Exogenous mechanisms of resistance

Class-specific efflux

Class-specific degradation/modification

Target protection/modification

Replacement with affinity target

Sequestration of target

Which bacteria are priority 1 (critical) on the WHO priority list?

Acinetobacter baumannii, carbapenem resistant

Pseudomonas aeruginosa, carbapenem resistant

Enterobacteriaceae, carbapenem resistant, ESBL producing

All gram negatives

What is the dual targeting approach?

Trying to target two things at once, either with two different drugs or ideally two in one drug (linking the two together to work as one)

Reduced resistance risk

Often PK issues when using two drugs

Example of dual targeting approach

Irresistin-16: two independent cellular targets.

CUrrently a Lead, shown efficacy against N. gonorrhoeae

What is the selective targeting approach?

Allow the use of relatively toxic antibiotics as systemic agents by making it only active at site of infection

Eg modification of colistin with ubiquicidin

Overview of Ceftazadime-Avibactam

New drug class of non-beta-lactam beta-lactamase inhibitor

DBO

Avibactam able to inhibit beta-lactamases from multiple resistant species

Not active against metallo-beta-lactamases though

Overview of Varobactam

Another non-beta-lactam beta-lactamase inhibitor

Combined with meropenem

Boronic acid

Complicated UTIs and pyelonephritis, hosp acquired pneumonia etc

Good against serine beta-lactamases

Attempting to develop one that works against MBLs

What is the Trojan Horse approach, and what is an example?

Bacteria tricked into taking up antibiotic due to drug being linked to siderophore

Cefiderocol example—type of cephalosporin

Mixed results regarding efficacy against resistant bacteria—can just mutate siderophore take-up