Laboratory of Translational Microbiology

Through our research, we aim to pave the way for a new era of precision medicine designed to effectively combat antibiotic resistance. To achieve this, our team employs a range of systems and synthetic biology techniques, including bioinformatics and genome engineering. Our primary objective is twofold. First, to gain a deeper understanding of how resistance evolves against new antimicrobials. In the past five years, we have made important contributions to the understanding of the evolution of resistance to antimicrobial peptides and to antibiotics in clinical development. For these studies, we have developed a new functional metagenomic method for studying horizontal gene transfer in microbial communities with the help of engineered bacteriophages. Second, we would like to understand how pathogens are spreading, in particular in the region of Eastern Europe. We studied the COVID-19 pandemic with the tools of genomic epidemiology and started to investigate the transmission dynamics of nosocomial infections, with a special focus on Acinetobacter baumannii. We are now using this knowledge to create innovative therapeutic strategies, with a particular focus on bacteriophages. Ultimately, our work aims to serve as a guide on how modern biological approaches can be harnessed to develop personalized treatments capable of tackling even the most resilient bacteria.

The establishment of our laboratory was supported by the National Biotechnology Laboratory and a grant from the Hungarian Centre of Excellence for Molecular Medicine (HCEMM). HCEMM is dedicated to molecular medicine-oriented research initiatives, with the goal of fostering positive changes in research culture and promoting regional development.

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We are seeking Postdocs and PhD students to join us. Contact Bálint Kintses if interested.

Research overview

Reprogrammed Bacteriophage Particle Assisted Multi-species Functional Metagenomics (DEEPMINE)

In our recent publication in Nature Microbiology, we introduced a new approach called Reprogrammed Bacteriophage Particle Assisted Multi-species Functional Metagenomics (DEEPMINE) to expand the functional metagenomic toolbox for studying microbial communities and by doing so, deepen our understanding of how antimicrobial resistance emerges. The traditional metagenomic screening approach for antibiotic resistance genes (ARGs) relies on laboratory strains of Escherichia coli as bacterial hosts, leaving us blind to ARGs that provide resistance specifically in clinically relevant pathogens. To address this issue, DEEPMINE employs modified bacteriophage transducing particles to deliver large metagenomic plasmid libraries into a wide range of bacterial species, allowing us to perform metagenomic screens in clinically relevant bacterial pathogens from the Enterobacteriaceae family. Through this approach, we identified several previously unreported ARGs with species-specific effects on antibiotic susceptibility. Additionally, our study revealed that newly approved or late-stage clinical development antibiotics  are just as prone to resistance formation as old antibiotics after decades of clinical use, highlighting the need for innovation and ongoing research into combating antibiotic resistance.

A single early introduction governed viral diversity in the second wave of SARS-CoV-2 epidemic in Hungary

In our paper we showed that retrospective evaluation of past waves of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic is key for designing optimal interventions against future waves and novel pandemics. Here, we reported on analyzing genome sequences of SARS-CoV-2 from the first two waves of the epidemic in 2020 in Hungary, mirroring a suppression and a mitigation strategy, respectively. Our analysis revealed that the two waves markedly differed in viral diversity and transmission patterns. Specifically, unlike in several European areas or in the USA, we found no evidence for early introduction and cryptic transmission of the virus in the first wave of the pandemic in Hungary. Despite the introduction of multiple viral lineages, extensive community spread was prevented by a timely national lockdown in March 2020. In sharp contrast, the majority of the cases in the much larger second wave can be linked to a single transmission lineage of the pan-European B.1.160 variant. This lineage was introduced unexpectedly early, followed by a 2-month-long cryptic transmission before a soar of detected cases in September 2020. Epidemic analysis revealed that the dominance of this lineage in the second wave was not associated with an intrinsic transmission advantage. This finding was further supported by the rapid replacement of B.1.160 by the alpha variant (B.1.1.7) that launched the third wave of the epidemic in February 2021. These findings collectively underscore the role of the founder effect, in conjunction with cryptic transmission, as the driving factors behind viral diversity, as opposed to recurrent international introductions or heightened transmissibility.

Evaluating the Risk of Resistance Evolution Against Novel Antimicrobials

Bacteria can share antibiotic resistance genes through a process known as horizontal gene transfer. This mode of spreading mobile resistance genes has proven to be the primary mechanism by which bacteria protect themselves from the effects of antibiotics, significantly contributing to the ongoing antibiotic crisis.

Our research focused on understanding the emergence of resistance genes against novel therapeutic approaches. We aimed to investigate how these resistance genes start to spread among human pathogens encountered in healthcare settings and within the human microbiota. One of our research projects, conducted in collaboration with the Pál and Papp Labs, centers on the horizontal transmission of resistance genes against cationic antimicrobial peptides (AMPs). While AMPs are promising therapeutic agents, they are also among the most ancient and efficient components of the innate immune defense strategy of multicellular organisms. This led us to the question why natural AMPs, integral to the human innate immune system, have remained effective for millions of years without the evolution of detectable resistance in several bacterial species. In contrast, clinical antibiotics tend to lose their effectiveness in a very short period of time.

Our study, published in Nature Microbiology, uncovered the presence of robust phylogenetic barriers to the horizontal transfer of AMP resistance genes in the human gut microbiota. This finding may provide a partial explanation for the persistence of AMP efficacy over extended evolutionary periods. Significantly, our work garnered recognition from the scientific community at Faculty 1000, and it has been included in the core collection of studies by the editorial board of Nature, signifying its importance in the context of gut microbiota research in 2019.

Augmenting Phage Therapeutic Potency by Shaping Phage-Human Interactions

 Therapeutically applied phages often face challenges that compromise their effectiveness upon administration, greatly hindering their clinical utility. At the same time, our body is teeming with phages: apparently there are no human organs inaccessible to them, including those previously considered as ‘sterile’, such as the cerebrospinal fluid. There are clearly evolutionary pathways by which phages can infiltrate our body and thrive within. However, the specific mechanisms by which they accomplish this remain uncertain. One of our main research directions is to gain a deeper insight into human-phage interactions. This knowledge can be harnessed to greatly enhance the potency of phage therapies. Our research focuses on two clinically important aspects of phage activity in the human body. First, we investigate how phages can achieve elevated predatory potential and increased persistence in the gut. Second, we delve into how certain phages can easily bypass the otherwise infamously impenetrable Blood-Brain Barrier. Exploration and utilization of the underlying genetic factors enabled us to genetically modify clinically viable phages in a way that enhances their therapeutic potential. Beyond their evident value in eradicating bacterial diseases, the rational manipulation of phage-human interactions unlocks unanticipated possibilities that further expand the clinical applicability of phage-based therapeutics.

Lab Members

Balint Kintses established his laboratory in 2019, with support from the Hungarian Centre of Excellence for Molecular Medicine (HCEMM). With over 18 years of research experience, including a four-year postdoctoral tenure at the University of Cambridge, Kintses has extensive experience. He has more than 25 publications, mostly in high profile journals, such as Nature Microbiology and Nature Communications. Furthermore, he has played a pivotal role in the prototype development of several biochemical methodologies, such as advanced microfluidic-based high-throughput screening and genome engineering methodologies, many of which have achieved notable success on the global stage.

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