Jordy E. Sulaiman
Postdoc Research Projects (UW-Madison)
1) Elucidating gut microbiota interactions that are robust to C. difficile strain variability and nutrient landscapes.
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Clostridioides difficile is an opportunistic human gut pathogen and is the leading cause of healthcare-associated infectious diarrhea. Fecal Microbiota Transplant (FMT) is an attractive alternative to antibiotics for treating C. difficile infection (CDI). However, each FMT sample is bound to some level of uncertainty in terms of efficacy and safety. It could also cause serious adverse health effects and unintentionally transfer antibiotic-resistant bacteria. These problems could be overcome using well-characterized microbial communities that have been standardized and optimized to inhibit C. difficile. However, there are variable successes in using defined consortia to treat CDI in clinical trials. One of the major factors contributing to this failure is that C. difficile strains display extreme genetic variability and confront a changeable nutrient landscape in the gut.
We characterized a set of C. difficile isolates from patients with CDI and also isolates from healthy individuals. By combining high-throughput experiments to build human gut communities with data-driven computational models, we map inter-species interactions shaping the growth of diverse C. difficile strains and toxin production in different nutrient environments. Using our computational model, we aim to design lower-richness anti-C. difficile communities that are robust against strain variation and nutrient landscapes and validate its effectiveness in vivo.
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2) Studying the long-term growth dynamics and evolutionary adaptations of C. difficile in human gut communities.
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The opportunistic pathogen C. difficile can transiently or persistently colonize the human gut for yearlong timescales, which contributes to the rising incidence of community-acquired C. difficile infections. Since human gut microbiota interactions are major variables influencing colonization ability, there is a critical need to understand the molecular and ecological mechanisms shaping C. difficile growth and its ability to coexist in communities over long timescales. By building communities from the bottom-up, we investigate the long-term growth dynamics of C. difficile for hundreds of generations in different communities and environmental contexts.
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Ph.D. Research Projects (HKUST)
1) Method development of studying persistence by proteomics
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Although we are now accumulating more observations regarding the behaviors of persisters and their formation mechanism, many important issues remain unanswered. Using state-of-the-art mass spectrometric methods, we aim to profile the proteome changes specific to persisters formation and identify the few proteins signature that plays important roles in persisters formation pathways.
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In our previous experiments, we have adopted the chemical pretreatment method to increase the number of persisters in E. coli population and developed a novel magnetic beads-based approach to isolate the persisters from the intact dead cells after lethal antibiotic treatment. We have obtained the proteome profile of persisters from planktonic E. coli culture through pretreatment with rifampin (inhibit RNA polymerases for DNA transcription), and identified some important proteins related to persistence.
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2) Study of highly tolerant evolved populations from cyclic antibiotic treatment
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There are different ways for a bacterial population to survive antibiotic assault, and one of them is by being in a dormant, persister state. Interestingly, when the survivors of antibiotic treatment are repeatedly regrown and retreated with the same antibiotic for several cycles, the new population will soon adapt to the treatment and become tolerant to the drug. We aim to characterize the high persistence phenotype of the evolved populations from cyclic antibiotic treatment and elucidate their mechanism of antibiotic tolerance through the combination of genome sequencing and proteomic analysis.
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We have conducted a preliminary study by following the evolution of E. coli under treatment with different antibiotics using the procedure that has been previously described. It is remarkable that the evolved populations showed a significant increase in survival under the antibiotic treatment only after a few cycles of "training". More surprisingly, this tolerance phenotype is acquired by only single point mutations in one of several genes. Evolution experiment with different antibiotics produce evolved populations with different mutations but leads to the same persistence phenotype.
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3) Resuscitation mechanism of persisters
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To date, far more research efforts have been devoted to study persister formation than to persister resuscitation. We do not really know how persisters revert to growing cells. What are the cellular processes involved? Are specific signals required to trigger these processes, or is there some inherent kinetics involved and resuscitation is merely a matter of time? The truth is, studying persisters resuscitation is problematic as the number of persisters is too low, only allowing for single-cell analysis - which could hardly give us information about the key players in the resuscitation process.
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Fortunately, through the evolution experiment (cyclic antibiotic treatment) that we conducted previously, we successfully isolated strains with high persisters population, providing new avenues to study the resuscitation of persisters. These populations containing a high number of persisters will have high survival under lethal antibiotic treatment and could be regrown on culture media and subsequently subjected for proteomic study.
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4) Evolution of MRSA under antibiotic combination treatment
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Staphylococcus aureus is a gram-positive bacterium that has long been recognized as one of the most important pathogens in human disease. In the early 1960s, new antibiotic methicillin was introduced to treat S. aureus, but within 2 years of its usage, the emergence of methicillin-resistant S. aureus (MRSA) was already reported. Since then, MRSA has spread and become endemic in most hospitals worldwide, paving its way as the top leading hospital-associated infection in the United States.
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Clinical treatments tend to involve several drugs, especially for patients with severe infections. Antibiotic combination treatment has been an attractive alternative as it could suppress the rapid emergence of resistance. Despite the well-known fact that repetitive antibiotic treatment will lead to tolerance and resistance in bacterial populations, the difference in the evolutionary path between those treated with a single drug and drug combination remains unaddressed. In our lab, we monitored the development of tolerance and resistance in MRSA by treating them with either single antibiotic treatment, or drug combination treatment, in a cyclic manner. Through proteomics, we compared the proteome profile of the population harboring different mutations; tolerance mutation alone, resistance mutation alone, and both tolerance and resistance mutations. The fact that these populations employ different mechanisms to survive antibiotic treatment suggests that the treatment strategy for these populations should be tailored depending on whether they possess tolerant mutation, resistant mutation, or both.
Funded with the General Research Fund, Research Grant Council, Grant No. 16102821 (Funding period from 2021-2024).
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5) Discovering novel compounds to inhibit and eradicate MRSA biofilms
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Like many other bacteria, MRSA could form biofilms that could protect themselves against antibiotic exposure. In collaboration with a marine biology laboratory, we are also interested in identifying novel compounds that are effective against MRSA biofilms and characterizing their mode of action using multi-omics technology.