Establishing the confluence of virulence and antibiotic resistance through antibiotic selection in Klebsiella pneumoniae

Background

The rising rates of antibiotic resistance limit the efficacy of life-saving antibiotics against all deadly infections but particularly against those caused by Gram-negative pathogens such as Klebsiella pneumoniae (KPN). KPN is a major nosocomial pathogen, driven by its’ ability to acquire and transmit antimicrobial resistance (AMR); where according to the CDC and WHO poses a critical threat to human health^(1,2,3). Critically, KPN has emerged as a predominant pathogen associated with bloodstream and respiratory infections in COVID-19 pneumoniae underscoring its relevance as a major clinical threat. As such, the rising rates of antibiotic resistance in K. pneumoniae have resulted in increasingly limited therapeutic options against this pathogen, where the recent introduction of Trojan-Horse drugs such as cefidericol represents a landmark shift in therapeutic strategies against multidrug resistant Kp.

Trojan horse (TH) antibiotics such as cefidericol exploit the critical necessity for iron uptake into the bacterial cell for infection in vivo. In Gram-negative bacteria, the acquisition of iron is mediated via the release of small molecules called siderophores which trap and transport iron via specialised outer membrane channels (IROMPS). Importantly, certain Kp clades associated with greater infectivity and disease severity endogenically express higher levels of both IROMPs and siderophores suggesting that these strains are potentially more receptive to TH antibiotic entry and likely to mutate these loci upon selection.

The genetic cascade which facilitates the release of siderophores and permeation of iron via IROMPS is mediated largely by the iron-responsive FUR regulator, where its’ loss is linked to reduced virulence. Similarly, recent studies also show that the transcriptional regulators EnvZ-OmpR, BaeSR and RamA which generally limit antibiotic permeation and virulence also contribute to reduced cefidericol susceptibility.

Taken together, we hypothesise that the usage of Trojan-horse antibiotics can select for the emergence of antibiotic resistant and highly virulent bacteria to drive the emergence of epidemic lineages via these regulatory changes.

Training Outcomes

The expected training outcomes will enable the student to train and gain expertise in bioinformatics, molecular bacteriology, immunology and in vivo work. This project addresses a key strategic priority area in strengthening AMR expertise, where the candidate will receive training in both bioinformatics and cutting edge molecular techniques. All supervisors have well-resourced labs and extensive experience in supervising and mentoring PhD students, which will provide for both the scientific and pastoral development of the candidate

References

1. Trojan Horse Antibiotics—A Novel Way to Circumvent Gram-Negative Bacterial Resistance? - PMC (nih.gov)

2. Nutritional immunity: the battle for nutrient metals at the host–pathogen interface | Nature Reviews Microbiology

3. Iron Acquisition Systems of Gram-negative Bacterial Pathogens Define TonB-Dependent Pathways to Novel Antibiotics - PMC (nih.gov)