Hospital-acquired infections and Antimicrobial Resistance
Anton Peleg is Professor of Infectious Diseases and Microbiology and Director of the Department of Infectious Diseases at the Alfred Hospital and Monash University. He is also the Infection and Inflammation theme leader for Monash Partners, and a research group leader in the Department of Microbiology, Monash University. His research spans clinical to basic research, with a focus on hospital-acquired infections, antimicrobial resistance, infections in immunocompromised hosts and understanding mechanisms of disease caused by hospital pathogens. He has a particular clinical interest in complex infections in highly vulnerable patient groups, including patients with cystic fibrosis, lung and stem cell transplant recipients, and infections in patients with burns or in intensive care.
Our research focuses on antimicrobial-resistant (AMR) and hospital-acquired infections and their causative organisms. The antibiotic development pipeline is very limited and now, more than ever, we need to identify new strategies and targets to prevent or treat AMR and hospital-acquired pathogens. Our research involves clinical, translational and basic science aspects of hospital-acquired infections.
Our laboratory research is focused on three main hospital-acquired pathogens, and we also focus on microbial biofilms and medical device infections.
1. Acinetobacter baumannii
A. baumannii is an opportunistic human pathogen causing both hospital and community acquired infections, responsible for a range of disease types including wound infections, pneumonia and bacteraemia. Ranked by the World Health Organisation as the most critical pathogenic threat to the future of human health, due to rampant levels of antibiotic resistance in many hospital-acquired A. baumannii strains, and their propensity to develop resistance to current therapeutics. There is currently only a limited understanding of the virulence factors responsible for the success of A. baumannii as a pathogen. The Peleg laboratory focus on not only elucidating the molecular mechanisms responsible for A. baumannii pathogenesis, but also understanding the host factors that contribute to its success. By enhancing our understanding of these unique host-pathogen interactions we aim to lead the development of novel therapies and assist in the prevention of these infections.
Our current research couples genetics, bioinformatics and phenotypic assays (including in vivo models) to elucidate the differences observed between clinical isolates responsible for hospital and community acquired infections, characterise putative virulence factors, understand the contribution of environmental factors, and the molecular mechanisms regulating gene expression both in vitro and in vivo, and examining how the host immune responses can modulate bacterial gene expression.
2. Staphylococcus aureus
S. aureus is one of the most common human bacterial pathogens, and is able to cause a wide range of life-threatening infections in the community and hospital setting. As a consequence of the rising rates of methicillin- resistant S. aureus (MRSA), agents such as vancomycin and daptomycin have been increasingly relied upon. Unfortunately, reduced susceptibility to these agents has now emerged. By using large-scale, whole-genome sequencing of clinical S. aureus isolates, whereby the first isolate is susceptible and the paired isolate is non-susceptible, we focus on describing the genetic evolution of antibiotic resistance in patients. Interestingly, we have also identified, using both mammalian and non-mammalian infection model systems, that these resistant strains are attenuated in virulence when compared to their susceptible progenitors but appear more persistent in vivo, mimicking what is observed clinically. We have identified a novel metabolic adaptation strategy used by S. aureus to simultaneously circumvent killing by daptomycin and attacks from host innate immune cells, which enhance bacterial survival during infection. Understanding the relationship between antibiotic resistance and host-pathogen interaction gives us insight into new strategies to prevent and treat infections caused by this organism.
3. Emerging antibiotic resistance and lateral gene transfer
The rapid dissemination of antibiotic resistance determinants across bacterial and fungal species threatens to return modern medicine to a pre-antibiotic era. As the levels of multi and pan drug resistance has continued to grow over recent years, so has our surveillance of hospital environments and specifically the appearance and transmission of bacterial strains harbouring genes responsible for antibiotic resistance. Worryingly, during the last decade we have increasingly observed the lateral transfer of genes promoting antibiotic resistance across not only different species but also different genera of Gram negative bacteria.
Using a combination of next generation sequencing paired with in vitro assessment of contemporary and historical clinical isolates, the Peleg lab aims to uncover the mechanisms responsible for this lateral transfer of antibiotic resistance genes, to understand not only the genetic context in which they are encoded, but also the ‘signals and triggers’ that promote their dissemination and the mechanisms by which they are mobilised from one genera to another.
By elucidating the drivers of these processes we can advise and direct clinicians and hospital practises, respectively, to minimise the potential for these ‘gene outbreaks’ and the dissemination of these dangerous genetic determinants.
4. Microbial biofilms and medical device infections
Another research interest of our group is to understand the role of biofilms in the pathogenesis of many hospital acquired infections: how bacteria and fungi adhere to medical devices and form biofilms, how this planktonic-biofilm phenotypic change leads to high resistance to antimicrobials and human defences, and what external factors (environmental aspect) and internal factors (cellular aspect) regulate biofilm formation of the microorganisms. Our current biofilm research has a very broad pathogen coverage, including the fungal pathogen C. albicans, gram-negative bacteria Klebsiella pneumoniae, A. baumannii and P. aeruginosa and gram-positive bacteria Staphylococcus epidermidis and S. aureus. We are currently studying biofilm formation and migration on ventricular assist device (VAD) drivelines, from both in vitro and in vivo aspects. Ventricular assist devices have been successfully used to manage acute and chronic end stage cardiac disease. Long-term VAD success is limited predominantly by the occurrence of exit-site infections and pocket infections, due to microbial biofilms formed on implanted drivelines. The specific biofilm growth mode equips the pathogens extreme resistance to conventional antimicrobial treatments and the human immune system, and is believed to be the cause of persistent infections. We work closely with engineers from Commonwealth Scientific and Industrial Research Organisation (CSIRO), and cardiac surgeons from the Alfred hospital, aiming to develop new antimicrobial strategies to prevent biofilm-related infections.
1. Impact of antimicrobial resistance on immune recognition of Staphylococcus aureus
2. Impact of antimicrobial resistance upon virulence and persistence in Staphylococcus aureus
3. Understanding the biology of Acinetobacter baumannii including;
- characterisation of small rnas and novel virulence factors
- defining the drivers of innate immune responses
4. Deciphering the contribution of different metabolic pathways to bacterial survival
5. Understanding the genetic and phenotypic drivers of lateral gene transfer in clinical isolates
Visit Professor Peleg's Monash research profile to see a full listing of current projects.
Molecular genetics of bacterial and fungal pathogens
Genomic, transcriptomic and metabolomic analyses of AMR bacteria
Zebrafish and murine models for the study of host-pathogen interactions, for S. aureus and A. baumannii, with models mimicking pneumonia and bacteraemia.
The roundworm (C. elegans) to assess virulence and to identify novel factors.
A full list of publications can be found at Google Scholar