A Boron-Dependent Antibiotic Derived from a Calcium-Dependent Antibiotic

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Antimicrobial Resistance

Background:

• Drug-resistant bacterial pathogens pose a significant global health threat.
• Calcium-dependent antibiotics (CDAs) offer novel mechanisms of action (MOA) against resistant bacteria.
• Calcium dependency limits the therapeutic potential of many CDAs.

Purpose of the Study:

• To engineer a synthetic analogue of laspartomycin C (LspC) with reduced or eliminated calcium dependence.
• To investigate alternative induction mechanisms for CDA activity.
• To develop a novel boron-dependent antibiotic.

Main Methods:

• Synthetic modification of laspartomycin C (LspC) to create analogue B1, replacing calcium-coordinating residues with serine.
• Induction of B1 activity using phenylboronic acid (PBA) to form a boronic ester.
• Characterization using thin-layer chromatography, mass spectrometry (MS), and nuclear magnetic resonance (NMR).
• Evaluation of antibacterial activity and MOA via complementation assays.

Main Results:

• A synthetic LspC analogue (B1) was created that functions independently of calcium, with activity induced by phenylboronic acid (PBA).
• B1 inhibits bacterial growth by sequestering undecaprenyl phosphate, the same MOA as LspC.
• B1 demonstrated comparable potency and efficacy to LspC against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE).

Conclusions:

• The conversion of a CDA to a boron-dependent antibiotic is feasible.
• This strategy offers a new approach for designing and controlling antibiotic function.
• The development of B1 provides a promising alternative for combating drug-resistant bacterial infections.