# Structure–Activity Relationship and Crystallographic Study of New Monobactams

## TL;DR

This paper explores new monobactam antibiotics and their interactions with bacterial proteins, revealing insights that could lead to more effective treatments.

## Contribution

The study introduces new monobactam derivatives and identifies novel binding interactions with penicillin-binding proteins.

## Key findings

- Certain monobactam derivatives showed activity against Staphylococcus aureus, a bacteria typically resistant to monobactams.
- Crystal structures revealed a halogen bond with a conserved threonine residue, suggesting a new mechanism for PBP inhibition.
- 2D similarity search identified potent inhibitors active against multiple drug-resistant bacteria.

## Abstract

Monobactams, a subclass of β-lactam antibiotics
with a monocyclic
scaffold, are uniquely resistant to hydrolysis by metallo-β-lactamases,
providing a distinct therapeutic advantage. Here, we report an in silico-based structure–activity relationship (SAR)
investigation of aztreonam-related monobactams. A focused library
of monobactam derivatives was synthesized and evaluated for inhibition
of penicillin-binding proteins (PBPs) and antibacterial activity.
Ten compounds, including aztreonam, were crystallized with truncated
PBP1b from Streptococcus pneumoniae, used as a model PBP. Potent PBP1b inhibitors were developed, although
high enzymatic potency was not always reflected in strong antibacterial
activity. Certain derivatives showed activity against Staphylococcus aureus, which is typically resistant
to monobactams. 2D similarity search identified potent inhibitors
active against Escherichia coli, Klebsiella pneumoniae, and Acinetobacter
baumannii. Crystal structures revealed previously
unrecognized binding interactions, including a halogen bond with a
conserved threonine residue, underscoring the potential of these interactions
to support the development of more potent PBP inhibitors.