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Evaluating the efficacy and mode of action of combinations of β-lactams to treat infections with multi-drug resistant Pseudomonas aeruginosa, Klebsiella pneumoniae and Escherichia coli.

School of Biology

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Dr P Coote No more applications being accepted Competition Funded PhD Project (Students Worldwide)

About the Project

There is a global requirement to identify novel treatments to combat multidrug-resistant (MDR) Gram-negative bacteria. Incidence of infections caused by these pathogens is rising and effective treatment is problematic resulting in increased morbidity and mortality. Few new treatment options are in the drug ‘pipeline’ so the use of combination treatments with two or more antibiotics is a realistic option. Combinations consisting of multiple antibiotics, usually of different classes, are employed clinically and have been extensively studied. In contrast, combinations of antibiotics from the same class, for example β-lactams, is under-explored, particularly with in vivo studies. The aim of this research is to employ an invertebrate infection model, Galleria mellonella larvae, to screen the efficacy of a range of β-lactam antibiotic combinations against MDR strains of Pseudomonas aeruginosa, Klebsiella pneumoniae and Escherichia coli. Notably, this type of in vivo efficacy screen is only possible because of the use of an invertebrate infection model - screening for efficacious combinations in mammalian models would not be possible due to ethical constraints and costs. Efficacious combinations that are identified by this approach will be further characterized by time-kill assays and synergy assays in vitro. The inhibitory mode of action of efficacious combinations will be determined by measuring: i) penicillin-binding protein inhibition; ii) the degradation of the individual antibiotics within the combinations upon exposure to MDR bacteria expressing β-lactamases via NMR, and iii) the effect antibiotic combinations have on the innate immune system of G mellonella. In each case, the effect of the combination will be compared to the effect of/on the individual drugs making up the combination.

Because there are large numbers of different β-lactams, this study is not proposing to screen every possible combination. A reasoned approach to selecting which β-lactams to test, and how many, has been made. In this study, two types of β-lactam combinations will be tested, and the project duration is planned to complete these:
1. Combinations limited to carbapenem antibiotics only. Preliminary data on dual carbapenem combination therapy on infections due to MDR, carbapenemase-producing strains of K. penumoniae has shown promise (Figure 1). There are 4 approved drugs in this class: meropenem, imipenem, doripenem and ertapenem. All dual, triple and 1 quadruple carbapenem combinations will be screened for enhanced efficacy against the bacteria listed above.

2. A selection of 6 different β-lactams. This entails screening of 15 dual, 20 triple, 15 quadruple, 6 quintuple and 1 sextuple combination(s). The 6 different β-lactams and the rationale for their selection for the screen are: 1. Aztreonam – selected because it is not susceptible to metallo-β-lactamases (MBLs) and there is evidence that it can synergise with third-generation cephalosporins [19 Sci Rep paper]. 2. Tazobactam – selected as a β-lactam that inhibits serine β-lactamases. 3. Piperacillin – selected as an anti-Pseudomonal penicillin. 4. Meropenem, and 5. Doripenem – selected as members of the carbapenem class with good activity versus susceptible Gram -ve pathogens but whose utility is threatened due to the rising incidence of carbapenemase-producing strains, and 6. Ceftazidime – selected as a readily available 3rd generation cephalosporin with good activity against susceptible Gram -ve bacteria, particularly P. aeruginosa, but is also failing due to the prevalence of ESBL and carbapenemase-producing pathogens.

Hypotheses to be investigated
1. β-lactam combination therapies can act as ‘resistance breakers’ and effectively treat real infections caused by multi-drug resistant Gram-negative bacteria.
2. β-lactam combinations offer enhanced efficacy versus carbapenemase-producing bacteria due to a hydrolytic ‘shielding’ effect.
3. β-lactam combinations stimulate the innate immune system to a greater extent than monotherapy and this contributes to their enhanced efficacy.

Aims of the proposed research project – The aims of this study are two-fold. Firstly, to utilize the G. mellonella infection model to identify combinations of β-lactams that show enhanced efficacy versus real infections with MDR Gram -ve pathogens. Secondly, to determine the inhibitory mode of action of potent β-lactam combinations.

Informal enquiries can be made to Dr Peter Coote via e-mail or telephone.
Email: [Email Address Removed]
Tel: (44) (0)1334 463406

Keywords: 3R’s; microbiology; antibiotic resistance; invertebrate infection model

Applications can be made online via our online portal-

Funding Notes

Funded by the School of Biology, University of St Andrews. The studentship covers tuition fees (Home and Overseas) and a living allowance for a duration of 3.5 years.

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