About the Project
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- https://www.st-andrews.ac.uk/study/apply/postgraduate/research/
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