Mapping the Protein Interaction Network in Methicillin-Resistant Staphylococcus aureus

Abstract

Mortality attributable to infection with methicillin-resistant Staphylococcus aureus (MRSA) has now overtaken the death rate for AIDS in the United States, and advances in research are urgently needed to address this challenge. We report the results of the systematic identification of protein-protein interactions for the hospital-acquired strain MRSA-252. Using a high-throughput pull-down strategy combined with quantitative proteomics to distinguish specific from nonspecific interactors, we identified 13,219 interactions involving 608 MRSA proteins. Consecutive analyses revealed that this protein interaction network (PIN) exhibits scale-free organization with the characteristic presence of highly connected hub proteins. When clinical and experimental antimicrobial targets were queried in the network, they were generally found to occupy peripheral positions in the PIN with relatively few interacting partners. In contrast, the hub proteins identified in this MRSA PIN that are essential for network integrity and stability have largely been overlooked as drug targets. Thus, this empirical MRSA-252 PIN provides a rich source for identifying critical proteins essential for network stability, many of which can be considered as prospective antimicrobial drug targets.

Discovery and optimization of a new class of pyruvate kinase inhibitors as potential therapeutics for the treatment of methicillin-resistant Staphylococcus aureus infections

“…2–4 This was based on the supposition that hub proteins are not only critical for bacterial survival but should be very sensitive to mutations 5 and targeting them should reduce the potential for development of resistance strains and species. In silico library screening, initially directed to putative binding sites unique to MRSA PK, combined with enzyme assays identified several active MRSA PK inhibitors including compound 1 6 (Fig.…”

Identification of Pyruvate Kinase in Methicillin-Resistant Staphylococcus aureus as a Novel Antimicrobial Drug Target

“…Moreover, given that hubs are generally essential for network integrity, they are expected to be less prone to genetic mutations and subsequent resistance emergence due to the network centrality-lethality rule (12). To this end, we recently mapped the architecture of a protein interaction network (PIN) between 608 proteins of S. aureus MRSA252 (7). As a result of this analysis, pyruvate kinase (PK), the product of a single-copy gene, was identified as a highly connected hub protein in MRSA.…”

Computational analysis of protein interaction networks for infectious diseases

“…It has been observed that topological features like DC and BC have gained much importance in serving as attractive drug targets [36,44,45]. However, despite their potential to locate such targets, these measures lack in the specificity and/or selectivity along with the high risk of side effects.…”

“…These core proteins were found to present in many subnetworks [84]. Thus, the organism's interaction network can be used to predict the function of the unannotated proteins or to map protein complexes and pathways involved in virulence, providing the directions for uncovering new drug targets [44,84,87]. Network topology was exploited to identify essential genes/proteins, which are crucial for replication, growth and viability of an organism, in different human host have been studied [94][95][96].…”