Interplay between Peptidoglycan Biology and Virulence in Gram-Negative Pathogens

Abstract

The clinical and epidemiological threat of the growing antimicrobial resistance in Gram-negative pathogens, particularly for β-lactams, the most frequently used and relevant antibiotics, urges research to find new therapeutic weapons to combat the infections caused by these microorganisms. An essential previous step in the development of these therapeutic solutions is to identify their potential targets in the biology of the pathogen. This is precisely what we sought to do in this review specifically regarding the barely exploited field analyzing the interplay among the biology of the peptidoglycan and related processes, such as β-lactamase regulation and virulence. Hence, here we gather, analyze, and integrate the knowledge derived from published works that provide information on the topic, starting with those dealing with the historically neglected essential role of the Gram-negative peptidoglycan in virulence, including structural, biogenesis, remodeling, and recycling aspects, in addition to proinflammatory and other interactions with the host. We also review the complex link between intrinsic β-lactamase production and peptidoglycan metabolism, as well as the biological costs potentially associated with the expression of horizontally acquired β-lactamases. Finally, we analyze the existing evidence from multiple perspectives to provide useful clues for identifying targets enabling the future development of therapeutic options attacking the peptidoglycan-virulence interconnection as a key weak point of the Gram-negative pathogens to be used, if not to kill the bacteria, to mitigate their capacity to produce severe infections.

Constructing and deconstructing the bacterial cell wall

“…The clinical importance of this connection cannot be overstated . The breadth of study of this β‐lactamase‐resistance response—from the molecular (antibiotic structure) to the macromolecular (protein‐ligand interaction, biochemical pathways) to the microbiological and the clinical—requires the medium of the comprehensive review . Here, we focus on the involvement of a family of important enzymes—the lytic transglycosylases—in peptidoglycan recycling and β‐lactamase induction …”

“…[218][219][220] The breadth of study of this β-lactamase-resistance response-from the molecular (antibiotic structure) to the macromolecular (protein-ligand interaction, biochemical pathways) to the microbiological and the clinical-requires the medium of the comprehensive review. [221][222][223][224][225][226][227][228] Here, we focus on the involvement of a family of important enzymes-the lytic transglycosylases-in peptidoglycan recycling and β-lactamase induction. 229,230 The lytic transglycosylases (LTs) are periplasmic enzymes (many, but not all, lipoproteins) that catalyze the deconstruction (hence "lytic") of the polymeric peptidoglycan through the nonhydrolytic cleavage of the glycan strand of the peptidoglycan (hence, the awkward "transglycosylase").…”

A secreted NlpC/P60 endopeptidase fromPhotobacterium damselaesubsp.piscicidacleaves the peptidoglycan of potentially competing bacteria

“…Peptidoglycan (PG) is a major component of the bacterial cell wall, essential for maintaining structural integrity and internal osmotic pressure, shaping the morphology of bacteria and providing support for anchoring other components of the cell envelope (1,2). PG forms a mesh-like structure that enwraps the bacterial cell, referred to as sacculus, which is composed of long chains of two alternating β(1-4) glycosidic-bonded glycans, N-acetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc), cross-linked by short stem peptides, either directly or through bridging peptides (1,(3)(4)(5). The stem peptides are usually 4-5 amino acids long, contain L-and D-amino acids and extend from MurNAc (1)(2)(3)(4).…”

A Francisella tularensis L,D-carboxypeptidase plays important roles in cell morphology, envelope integrity, and virulence

“…PG homeostasis is extremely important, as mutations in any one of these enzymes can result in altered cell morphology, changes in cell membrane integrity, and reduced ability to replicate and divide (1). Importantly, a recent review highlighted the largely neglected field of Gram-negative bacterial PG synthesis and recycling, particularly given the growing threat of antimicrobial resistance and association of PG homeostasis with virulence (13). For example, Acinetobacter baumannii penicillin-binding protein (PBP) mutants were unable to survive in vitro or in vivo and were more sensitive to complement-mediated killing than wild-type bacteria (14) and Helicobacter pylori PG hydrolase (AmiA) mutants were unable to colonize mouse stomach tissue (15).…”