scholarly journals The Penicillin-Binding Protein PbpP Is a Sensor of β-Lactams and Is Required for Activation of the Extracytoplasmic Function σ Factor σP in Bacillus thuringiensis

mBio ◽  
2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Kelsie M. Nauta ◽  
Theresa D. Ho ◽  
Craig D. Ellermeier
Keyword(s):  
Cell Wall ◽  
Bacillus Thuringiensis ◽  
Bacterial Infections ◽  
Binding Proteins ◽  
Binding Protein ◽  
Penicillin Binding Protein ◽  
Content Type ◽  
Penicillin Binding Proteins ◽  
Σ Factor ◽  
The Cross

ABSTRACT β-Lactams are a class of antibiotics that target the synthesis of peptidoglycan, an essential component of the cell wall. β-Lactams inhibit the function of penicillin-binding proteins (PBPs), which form the cross-links between strands of peptidoglycan. Resistance to β-lactams complicates the treatment of bacterial infections. In recent years, the spread of β-lactam resistance has increased with growing intensity. Resistance is often conferred by β-lactamases, which inactivate β-lactams, or the expression of alternative β-lactam-resistant PBPs. σP is an extracytoplasmic function (ECF) σ factor that controls β-lactam resistance in the species Bacillus thuringiensis, Bacillus cereus, and Bacillus anthracis. σP is normally held inactive by the anti-σ factor RsiP. σP is activated by β-lactams that trigger the proteolytic destruction of RsiP. Here, we identify the penicillin-binding protein PbpP and demonstrate its essential role in the activation of σP. Our data show that PbpP is required for σP activation and RsiP degradation. Our data suggest that PbpP acts as a β-lactam sensor since the binding of a subset of β-lactams to PbpP is required for σP activation. We find that PbpP likely directly or indirectly controls site 1 cleavage of RsiP, which results in the degradation of RsiP and, thus, σP activation. σP activation results in increased expression of β-lactamases and, thus, increased β-lactam resistance. This work is the first report of a PBP acting as a sensor for β-lactams and controlling the activation of an ECF σ factor. IMPORTANCE The bacterial cell envelope is the target for numerous antibiotics. Many antibiotics target the synthesis of peptidoglycan, which is a central metabolic pathway essential for bacterial survival. One of the most important classes of antibiotics has been β-lactams, which inhibit the transpeptidase activity of penicillin-binding proteins to decrease the cross-linking of peptidoglycan and the strength of the cell wall. While β-lactam antibiotics have historically proven to be effective, resistance to β-lactams is a growing problem. The ECF σ factor σP is required for β-lactam resistance in B. thuringiensis and close relatives, including B. anthracis. Here, we provide insight into the mechanism of activation of σP by β-lactams.

scholarly journals Increasing Ceftriaxone Resistance and Multiple Alterations of Penicillin-Binding Proteins among Penicillin-Resistant Streptococcus pneumoniae Isolates in Taiwan

2007 ◽  
Vol 51 (9) ◽  
pp. 3404-3406 ◽  
Author(s):  
Cheng-Hsun Chiu ◽  
Lin-Hui Su ◽  
Yhu-Chering Huang ◽  
Jui-Chia Lai ◽  
Hsiu-Ling Chen ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Amino Acid ◽  
Binding Proteins ◽  
Binding Protein ◽  
Penicillin Binding Protein ◽  
Penicillin Binding Proteins

ABSTRACT The rate of nonsusceptibility of penicillin-resistant Streptococcus pneumoniae strains to ceftriaxone increased significantly in Taiwan in 2005. Approximately 90% of the ceftriaxone-nonsusceptible isolates were found to be of four major serotypes (serotypes 6B, 14, 19F, and 23F). Seven amino acid alterations in the penicillin-binding protein 2B transpeptidase-encoding region specifically contributed to the resistance.

scholarly journals Penicillin-binding proteins and carboxypeptidase/transpeptidase activities in Proteus vulgaris P18 and its penicillin-induced stable L-forms

1982 ◽  
Vol 152 (3) ◽  
pp. 1042-1048
Author(s):  
A Rousset ◽  
M Nguyen-Distèche ◽  
R Minck ◽  
J M Ghuysen
Keyword(s):  
Plasma Membrane ◽  
Binding Proteins ◽  
Binding Protein ◽  
Penicillin Binding Protein ◽  
Proteus Vulgaris ◽  
Penicillin Binding Proteins

The originally penicillin-induced, wall-less stable L-forms of Proteus vulgaris P18, isolated by Tulasne in 1949 and since then cultured in he absence of penicillin, have kept the ability to synthesize the seven penicillin-binding proteins and the various DD- and LD-peptidase activities found in the parental bacteria and known to be involved in wall peptidoglycan metabolism. The stable L-forms, however, secrete during growth both the highly penicillin-sensitive, DD-carboxy-peptidase-transpeptidase penicillin-binding protein PBP4 (which in normal bacteria is relatively loosely bound to the plasma membrane) and the penicillin-insensitive LD-carboxypeptidase (which in normal bacteria is located in the periplasmic region).

scholarly journals FmhA and FmhC of Staphylococcus aureus incorporate serine residues into peptidoglycan cross-bridges

2020 ◽  
Vol 295 (39) ◽  
pp. 13664-13676 ◽  
Author(s):  
Stephanie Willing ◽  
Emma Dyer ◽  
Olaf Schneewind ◽  
Dominique Missiakas
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Binding Proteins ◽  
Penicillin Binding Proteins ◽  
Daughter Cells ◽  
Cross Bridge ◽  
Resistant Strains ◽  
The Cross ◽  
Cross Bridges ◽  
Adjacent Wall

Staphylococcal peptidoglycan is characterized by pentaglycine cross-bridges that are cross-linked between adjacent wall peptides by penicillin-binding proteins to confer robustness and flexibility. In Staphylococcus aureus, pentaglycine cross-bridges are synthesized by three proteins: FemX adds the first glycine, and the homodimers FemA and FemB sequentially add two Gly-Gly dipeptides. Occasionally, serine residues are also incorporated into the cross-bridges by enzymes that have heretofore not been identified. Here, we show that the FemA/FemB homologues FmhA and FmhC pair with FemA and FemB to incorporate Gly-Ser dipeptides into cross-bridges and to confer resistance to lysostaphin, a secreted bacteriocin that cleaves the pentaglycine cross-bridge. FmhA incorporates serine residues at positions 3 and 5 of the cross-bridge. In contrast, FmhC incorporates a single serine at position 5. Serine incorporation also lowers resistance toward oxacillin, an antibiotic that targets penicillin-binding proteins, in both methicillin-sensitive and methicillin-resistant strains of S. aureus. FmhC is encoded by a gene immediately adjacent to lytN, which specifies a hydrolase that cleaves the bond between the fifth glycine of cross-bridges and the alanine of the adjacent stem peptide. In this manner, LytN facilitates the separation of daughter cells. Cell wall damage induced upon lytN overexpression can be alleviated by overexpression of fmhC. Together, these observations suggest that FmhA and FmhC generate peptidoglycan cross-bridges with unique serine patterns that provide protection from endogenous murein hydrolases governing cell division and from bacteriocins produced by microbial competitors.

scholarly journals Affinity of Tomopenem (CS-023) for Penicillin-Binding Proteins in Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa

2008 ◽  
Vol 53 (3) ◽  
pp. 1238-1241 ◽  
Author(s):  
Tetsufumi Koga ◽  
Chika Sugihara ◽  
Masayo Kakuta ◽  
Nobuhisa Masuda ◽  
Eiko Namba ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Staphylococcus Aureus ◽  
Pseudomonas Aeruginosa ◽  
Binding Proteins ◽  
Binding Protein ◽  
Penicillin Binding Protein ◽  
Penicillin Binding Proteins ◽  
E Coli ◽  
High Affinity

ABSTRACT Tomopenem (formerly CS-023), a novel 1β-methylcarbapenem, exhibited high affinity for penicillin-binding protein (PBP) 2 in Staphylococcus aureus, PBP 2 in Escherichia coli, and PBPs 2 and 3 in Pseudomonas aeruginosa, which are considered major lethal targets. Morphologically, tomopenem induced spherical forms in E. coli and short filamentation with bulges in P. aeruginosa, which correlated with the drug's PBP profiles. The potential of resistance of these bacteria to tomopenem was comparable to that to imipenem.

scholarly journals bla ROB-1 Presence on pB1000 in Haemophilus influenzae Is Widespread, and Variable Cefaclor Resistance Is Associated with Altered Penicillin-Binding Proteins

2010 ◽  
Vol 54 (11) ◽  
pp. 4945-4947 ◽  
Author(s):  
Stephen G. Tristram ◽  
Rachael Littlejohn ◽  
Richard S. Bradbury
Keyword(s):  
Haemophilus Influenzae ◽  
North American ◽  
Binding Proteins ◽  
Binding Protein ◽  
Low Frequency ◽  
Penicillin Binding Protein ◽  
Penicillin Binding Proteins

ABSTRACT Plasmid pB1000 is a small replicon recently identified as bearing bla ROB-1 in animal and human Pasteurellaceae in Spain. We identified pB1000 in 11 bla ROB-1-positive Australian and North American Haemophilus influenzae isolates, suggesting a wider role for pB1000 in disseminating bla ROB-1. Native H. influenzae conjugative elements can mobilize plasmids similar to pB1000 at a low frequency of 10−8, and this might account for the infrequency of bla ROB-1 compared to the rate of occurrence of bla TEM-1. Altered penicillin-binding protein 3 was associated with an increased cefaclor MIC in 3 isolates.

scholarly journals The ponA Gene of Enterococcus faecalis JH2-2 Codes for a Low-Affinity Class A Penicillin-Binding Protein

2004 ◽  
Vol 186 (13) ◽  
pp. 4412-4416 ◽  
Author(s):  
Colette Duez ◽  
Séverine Hallut ◽  
Noureddine Rhazi ◽  
Séverine Hubert ◽  
Ana Amoroso ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Enterococcus Faecalis ◽  
Binding Proteins ◽  
Binding Protein ◽  
Penicillin Binding Protein ◽  
Penicillin Binding Proteins ◽  
Class A ◽  
Lipid Ii

ABSTRACT A soluble derivative of the Enterococcus faecalis JH2-2 class A PBP1 (*PBP1) was overproduced and purified. It exhibited a glycosyltransferase activity on the Escherichia coli 14C-labeled lipid II precursor. As a dd- peptidase, it could hydrolyze thiolester substrates with efficiencies similar to those of other class A penicillin-binding proteins (PBPs) and bind β-lactams, but with k 2/K (a parameter accounting for the acylation step efficiency) values characteristic of penicillin-resistant PBPs.

scholarly journals Crystal Structures of Penicillin-Binding Protein D2 fromListeria monocytogenesand Structural Basis for Antibiotic Specificity

2018 ◽  
Vol 62 (9) ◽  
Author(s):  
Jae-Hee Jeong ◽  
Hyung Jin Cha ◽  
Yeon-Gil Kim
Keyword(s):  
Crystal Structures ◽  
Bacterial Infections ◽  
Binding Protein ◽  
Bacterial Pathogen ◽  
Penicillin G ◽  
Structural Basis ◽  
Side Chains ◽  
Penicillin Binding Protein ◽  
Content Type ◽  
Highly Correlated

ABSTRACTβ-Lactam antibiotics that inhibit penicillin-binding proteins (PBPs) have been widely used in the treatment of bacterial infections. However, the molecular basis underlying the different inhibitory potencies of β-lactams against specific PBPs is not fully understood. Here, we present the crystal structures of penicillin-binding protein D2 (PBPD2) fromListeria monocytogenes, a Gram-positive foodborne bacterial pathogen that causes listeriosis in humans. The acylated structures in complex with four antibiotics (penicillin G, ampicillin, cefotaxime, and cefuroxime) revealed that the β-lactam core structures were recognized by a common set of residues; however, the R1 side chains of each antibiotic participate in different interactions with PBPD2. In addition, the structural complementarities between the side chains of β-lactams and the enzyme were found to be highly correlated with the relative reactivities of penam or cephem antibiotics against PBPD2. Our study provides the structural basis for the inhibition of PBPD2 by clinically important β-lactam antibiotics that are commonly used in listeriosis treatment. Our findings imply that the modification of β-lactam side chains based on structural complementarity could be useful for the development of potent inhibitors against β-lactam-resistant PBPs.

scholarly journals A Mother Cell-Specific Class B Penicillin-Binding Protein, PBP4b, in Bacillus subtilis

2004 ◽  
Vol 186 (1) ◽  
pp. 258-261 ◽  
Author(s):  
Yuping Wei ◽  
Derrell C. McPherson ◽  
David L. Popham
Keyword(s):  
Bacillus Subtilis ◽  
Rna Polymerase ◽  
Mother Cell ◽  
Binding Proteins ◽  
Binding Protein ◽  
Specific Class ◽  
Penicillin Binding Protein ◽  
Penicillin Binding Proteins ◽  
Peptidoglycan Structure ◽  
Class B

ABSTRACT The Bacillus subtilis genome encodes 16 penicillin-binding proteins (PBPs), some of which are involved in synthesis of the spore peptidoglycan. The pbpI (yrrR) gene encodes a class B PBP, PBP4b, and is transcribed in the mother cell by RNA polymerase containing σE. Loss of PBP4b, alone and in combination with other sporulation-specific PBPs, had no effect on spore peptidoglycan structure.

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