Selective targeting of drug-resistant pathogens without affecting the microbiota (360G-Wellcome-204337_Z_16_Z)

A key strategy in mitigating the impact of antibiotic resistance is to limit the use of broad-spectrum antibiotics1. The reasons for this are three-fold: 1, reduced use of broad-spectrum drugs limits the spread of resistance1; 2, broad-spectrum antibiotics disrupt the microbiota, attenuating immunity against bacterial pathogens2,3. 3, disruption of the microbiota pre-disposes to infection by drug-resistant pathogens1. For example, ciprofloxacin causes gut dysbiosis and pre-disposes to C. difficile infection, which has a mortality rate of up to 30% and costs >€30K per patient to treat in European hospitals4,5. Therefore, where possible, infections are treated with narrow- spectrum antibiotics, which are less damaging to the microbiota1. Despite this, 3.5 million daily doses of fluoroquinolone antibiotics, such as ciprofloxacin, are prescribed in the UK1, in part because early empirical therapy with broad-spectrum antibiotics, together with a β-lactam, is recommended for severe infections such as sepsis and hospital-associated pneumonia (HAP), because it significantly enhances patient survival rates6,7. The use of the broad-spectrum antibiotic protects against pathogens expressing β-lactamase. Therefore, there is an unmet need for antibiotics that selectively target pathogens without disrupting the microbiota. The aim of this project is to use antibiotic resistance as an opportunity to enhance antibiotic specificity, by generating a novel antibiotic that selectively kills bacteria that express β-lactamase, without damaging the host microbiota. The key goals of this proposal are to generate an antibiotic that is 1, inactive against bacteria which do not express β-lactamase 2, is highly active against bacteria which do express β-lactamase 3, is chemically stable in host tissues and 4, is non-toxic to host cells. This approach is expected to have the following clinical impact: 1, in the case of HAP or sepsis, Ceph-C could replace ciprofloxacin in combination with a β-lactam, to cover for resistant bacteria before culture results are available. In this approach, active ciprofloxacin is only liberated when and where necessary, minimising disruption to the host flora; 2, Ceph-C could provide an effective mechanism to selectively target resistant bacteria causing recurrent (e.g. UTI) or chronic (e.g. cystic fibrosis) infections, which require frequent or prolonged periods of antibiotic therapy, without disturbing the microbiota.