Penicillin-Binding Protein 3 Inserts in E.coli:A Growing Burden of Underreported Threat

Introduction

Penicillin-binding proteins (PBPs) synthesize and remodel the peptidoglycan layer of the bacterial cell wall, which maintain cell shape and resist internal pressure. Bacteria express multiple PBPs (PBP1–PBP7), with functions varying across species. Among these, PBP-3 is vital in gram-negative bacteria like E. coli as it is a central part of the divisome complex that drives cell division. (1)

Characteristics of PBP3 in E. coli

Gram-negative bacteria like Escherichia coli has PBP3, also known as FtsI (Filamentous temperature-sensitive mutant I), a transpeptidase that forms cross-links between peptidoglycan strands and is essential for cell wall construction at the division site. PBP3 is a primary target of β-lactam antibiotics and thereby disrupts septum formation, leading to filamentous, non-dividing bacterial cells and eventual bacterial cell death. (2,3) Over the years, E. coli has developed resistance to β-lactam antibiotics, that reduce the binding affinity of antibiotics to PBP3 site, contributing to antibiotic resistance additionally along with β-lactamases/Carbapenemase. (4)

Prevalence of PBP3 inserts in E. coli Clinical Isolates

There is a growing burden of PBP3 inserts in E. coli which are contributing towards AMR. Studies have reported a high prevalence of E. coli clinical isolates in India with structural changes in the PBP3 protein. These changes involve insertions of additional amino acids, commonly YRIN or YRIK*, that reduce its binding affinity to β-lactam antibiotics caused by mutations in the ftsI gene, which encodes PBP3. (5,6) A study by Bakthavatchalam et al. reported 4-amino-acid insert in PBP3 was detected in 97% (n = 263/270) of E. coli Indian isolates regardless of the type of carbapenemase expressed [NDM and/or OXA-48 like producers, n = 243/250; solely OXA-48-like producers, n = 20/20]. (7)

Clinical Impact of PBP3-Mediated Resistance on β-Lactam Antibiotics

Over time, E. coli has developed resistance to β-lactam antibiotics such as ceftazidime, avibactam, and aztreonam, primarily due to PBP3 mutations involving amino acid inserts. These PBP3 inserts have led to significantly elevated Minimum Inhibitory Concentrations (MICs). In the case of the aztreonam/avibactam combination, MICs exceeding 4 mg/L meet the CLSI resistance threshold. (8) This elevation impairs microbiological efficacy, resulting in reduced drug effectiveness and increasing the likelihood of suboptimal clinical outcomes, such as prolonged treatment or the need for alternative therapies. Infections may persist or recur, highlighting the clinical challenge posed by such resistance. (9,10) Complicated Infections are associated with reduced β-lactam affinity in Gram-negative bacteria; and lead to longer hospital and ICU stays and increased mortality due to delayed and less effective treatment. (11)

Option for Targeting PBP3 inserts in E. coli Clinical Isolates

With rising PBP3-mediated resistance to β-lactam antibiotics such as ceftazidime-avibactam and aztreonam, there is a critical need for alternative therapeutic options. One such agent is plazomicin, an aminoglycoside that works by binding to the 30S ribosomal subunit, thereby inhibiting bacterial protein synthesis. Unlike most newer antibiotics that act through penicillin-binding proteins (PBPs), plazomicin's mechanism is independent of the peptidoglycan pathway targeted by β-lactams. This distinct mode of action gives plazomicin potential as an effective alternative in treating infections caused by PBP3-altered, β-lactam-resistant strains. (12)

Conclusion

• With declining E. coli susceptibility to β-lactams, exploring therapies with new mechanisms is vital to address the growing challenge of antimicrobial resistance.
• Plazomicin, an aminoglycoside, inhibits protein synthesis by targeting the 30S ribosomal subunit, offering an effective alternative against β-lactam-resistant E. coli due to its distinct mechanism.
• Plazomicin, an aminoglycoside, inhibits protein synthesis by targeting the 30S ribosomal subunit, approved for complicated urinary tract infections (cUTIs) and pyelonephritis, emerged as a promising agent against multidrug-resistant E. coli, offering a novel treatment option for E. coli isolates with PBP3 inserts.

*Abbreviation – Y, Tyrosine; R, Arginine; I, Isoleucine; N, Asparagine; K, Lysine; T, Threonine; P, Proline

Reference:

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