Role and regulation of peptidoglycan synthases in enterococcal antimicrobial resistance

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Principal Investigator: CHRISTOPHER J KRISTICH
Organization: MEDICAL COLLEGE OF WISCONSIN
Fiscal Year: 2024
Award: $476,642
Funding agency: National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY
The continued and inevitable emergence of antibiotic resistance demands a vigorous and sustained
effort to identify fundamentally new targets and strategies for innovative antimicrobial therapeutics.
Antibiotic-resistant enterococci are major causes of hospital-acquired infections. Enterococci are
successful hospital-acquired pathogens in part because of their intrinsic resistance to commonly used
antibiotics that target the bacterial cell envelope, such as cephalosporins. However, many questions
remain regarding the genetic and biochemical basis for cephalosporin resistance in enterococci.
Previous work revealed key roles for two signal transduction systems - the IreK transmembrane
kinase and the CroS/R two-component system - in regulation of cephalosporin resistance, but the
downstream effectors in the signaling pathways that drive cephalosporin resistance remain unknown.
In preliminary studies we showed that two penicillin-binding proteins – enzymes that synthesize
peptidoglycan – are each essential for cephalosporin resistance, yet are functionally distinct from
each other. The mechanisms by which the activity of these penicillin-binding proteins are regulated in
enterococci are unknown, although current models point to the possibility that these penicillin-binding
proteins exist as components of multiprotein peptidoglycan synthase complexes. Our data suggest
that the IreK and CroS/R signaling systems are responsible for regulation of penicillin-binding protein
activity to promote cephalosporin resistance. The major knowledge gaps to be addressed are that (i)
the composition and activity of the peptidoglycan synthases in response to cephalosporin stress are
unknown; (ii) a definitive link between IreK or CroS/R and the peptidoglycan synthases has not been
established; and (iii) the mechanisms by which cephalosporins induce lethality when one
peptidoglycan synthase is impaired is unknown. The research proposed here is designed to elucidate
new insights into the roles and regulation of peptidoglycan synthases in the biological processes that
drive enterococcal cephalosporin resistance. By doing so, we will provide new insights into the
fundamental biological processes that drive key antibiotic resistance in enterococci and define new
targets for innovative therapeutics designed to impair enterococcal cephalosporin resistance.

Terms: <Address><Antibiotic Agents><Antibiotic Drugs><Antibiotic Resistance><Antibiotics><Antimicrobial Resistance><Automobile Driving><Bacterial Antibiotic Resistance><Beta-Lactam resistant><Binding Proteins><Biochemical><Biological Function><Biological Process><Cell Communication and Signaling><Cell Signaling><Cell Wall><Cephalosporin Resistance><Cephalosporins><Classification><Clinical><Complex><Cytoplasmic Protein><Data><Development><Disabling><E faecalis><E faecium><E. faecalis><E. faecium><Enterococcus><Enterococcus faecalis><Enterococcus faecium><Enzyme Gene><Enzymes><Exhibits><Foundations><Future><Generalized Growth><Genetic><Gram-Positive Bacteria><Growth><Healthcare><Hospital Infections><Hospital acquired infection><Hospitals><Hydrolase><Hydrolase Family Gene><Hydrolase Gene><Impairment><Infection><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Kinases><Knowledge><LE-Enzyme><Ligand Binding Protein><Ligand Binding Protein Gene><Link><MRSA><Mediating><Membrane><Methicillin Resistant S. Aureus><Miscellaneous Antibiotic><Modeling><Mucopeptide Amidohydrolase><Multi-Drug Resistance><Multidrug Resistance><Multiple Drug Resistance><Multiple Drug Resistant><Murein><Murein Hydrolase><N-Acetylmuramoyl-L-alanine Amidase><Nosocomial Infections><Penicillin-Binding Proteins><Peptidoglycan><Peptidoglycan Hydrolase><Peptidoglycan amidohydrolase><Phosphorylation><Phosphotransferase Gene><Phosphotransferases><Protein Binding><Protein Phosphorylation><Proteins><Regulation><Reporting><Research><Resistance><Resistance to Multi-drug><Resistance to Multidrug><Resistance to Multiple Drug><Resistance to antibiotics><Resistant to Multiple Drug><Resistant to antibiotics><Resistant to multi-drug><Resistant to multidrug><Role><S faceium><S faecalis><S faecium><S. faceium><S. faecalis><S. faecium><Safety><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Streptococcus Group D><Streptococcus enterococcus group><Streptococcus faceium><Streptococcus faecalis><Streptococcus faecium><Stress><System><Systematics><Testing><Therapeutic><Tissue Growth><Transphosphorylases><United States><Vancomycin resistant enterococcus><Vancomycin-resistant enterococci><Work><anti-microbial><anti-microbial resistant><antibiotic drug resistance><antibiotic resistance emergence><antibiotic resistant><antibiotic resistant bacteria><antibiotic resistant pathogen><antimicrobial><b lactam resistance><b-lactam resistant><bacterial antibiotic resistant><bacterial resistance to antibiotic><bactericidal><bactericide><beta lactam antibiotic><beta-Lactam Resistance><beta-Lactams><biological signal transduction><bound protein><cell envelope><cephalosporin resistant><clinical relevance><clinical significance><clinically relevant><clinically significant><crosslink><design><designing><developmental><driving><drug resistant pathogen><emerging antibiotic resistance><experience><health care><innovate><innovation><innovative><insight><institutional infection><interventional strategy><membrane structure><methicillin resistance Staphylococcus aureus><methicillin resistant Staphylococcus aureus><methicillin resistant strains of Staphylococcus aureus><multi-drug resistant><multidrug resistant><mutant><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><ontogeny><pathogen><programs><resistance to anti-microbial><resistance to b lactam><resistance to beta-lactam><resistance to cephalosporin><resistance to β-Lactam><resistant><resistant to antimicrobial><resistant to b lactam><resistant to beta-lactam><resistant to cephalosporin><resistant to β-Lactam><response><social role><vancomycin resistance enterococci><vancomycin resistance in enterococci><β lactam antibiotic><β-Lactam Resistance><β-Lactam resistant><β-Lactams>