understand how the lung environment affects colistin treatment efficacy and to develop new therapeutic strategies to improve patient outcomes

Cystic fibrosis (CF) affects >10,000 people in the UK. Early mortality characterises the disease, largely
driven by chronic lung infection and inflammatory airway wall damage. By adulthood >60% patients
are chronically infected with the Gram-negative organism, Pseudomonas aeruginosa (Pa). Current
therapy is limited, and once infection is chronic, the best that can be achieved is 'suppression' of
bacterial load, usually with inhaled antimicrobials. The Strategic Research Centre for Pa infection
was established by Prof Jane C Davies, with a focus on improving understanding of pathogenic
mechanisms and therapies. Its partnership with the Royal Brompton Hospital's CF clinic, one of the
largest in Europe, through senior clinical academics, underpins the strong translational focus of the
programme. The narrow pipeline of new antibiotics under development means that work to improve
efficacy of existing agents is urgently needed.
Colistin is the polymyxin antibiotic used most commonly to control chronic P. aeruginosa infection in
CF. Unfortunately, whilst colistin is usually effective in suppressing infection, it is almost never able
to clear P. aeruginosa from the lungs once chronic infection is established. Intravenous colistin is
also used as a 'last-resort' agent in severe disease, and thus, the emergence of resistance to
polymyxin antibiotics is a growing concern. Efforts to improve colistin efficacy have been hampered
by a poor understanding of the antibiotic's mode of action and the lack of knowledge around the
impact that the host environment has on bacterial susceptibility. Recent work from the Edwards lab,
based in the MRC Centre for Molecular Bacteriology and Infection, has revealed that colistin targets
LPS in both the outer and cytoplasmic membranes, leading to bacterial lysis and killing (Sabnis et al.,
2019). We have also shown that colistin resistance due to the mobile colistin resistance (MCR) family
of LPS modifying enzymes (Liu et al., 2016) is due to modification of LPS at the cytoplasmic
membrane (Sabnis et al., 2019).
We exploited this information to develop a combination therapeutic approach to enhance colistin
activity. We found that the experimental antibiotic murepavadin caused the accumulation of LPS in
the cytoplasmic membrane of P. aeruginosa, which sensitised the bacterium >1000-fold to colistin mediated killing. Given the geographical heterogeneity in airway deposition of inhaled agents
related to airway narrowing and mucus plugging, and the resulting variability in drug concentrations,
successful approaches to enhance efficacy of lower drug concentrations could have direct clinical
impact.
The crucial next step in this work is to determine how the host environment influences LPS
processing and transport, which we hypothesise will have significant effects on colistin susceptibility
and therefore treatment outcomes. For example, during this work, we found that LPS released by
bacteria exposed to colistin can sequester the antibiotic, rendering it ineffective. We also found that
the presence of human serum renders P. aeruginosa tolerant of colistin. These findings indicate that
colistin efficacy is affected by the in vivo environment, but this requires further investigation.