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Nanomechanics of Drug-target Interactions and Antibacterial Resistance Detection
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Alkyl-Aryl-Vancomycins: Multimodal Glycopeptides with Weak Dependence on the Bacterial Metabolic State

Paramita Sarkar1, Debajyoti Basak1, Riya Mukherjee1

  • 1Antimicrobial Research Laboratory, New Chemistry Unit and School of Advanced Materials, Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Jakkur, Bengaluru 560064, Karnataka, India.

Journal of Medicinal Chemistry
|July 7, 2021
PubMed

Insights

New alkyl-aryl-vancomycins (AAVs) show potent activity against resistant bacteria. The lead compound AAV-qC10 eradicates biofilms and persister cells, offering a promising new therapeutic strategy for drug-resistant infections.

Area of Science:

  • Microbiology
  • Medicinal Chemistry
  • Pharmacology

Background:

  • Growing resistance to last-resort antibiotics like vancomycin is a major public health threat.
  • Bacterial biofilms and persister cells pose significant challenges to conventional antibiotic therapies.
  • Novel therapeutic agents are urgently needed to combat multidrug-resistant Gram-positive bacterial infections.

Purpose of the Study:

  • To develop and characterize novel vancomycin derivatives with enhanced activity against resistant bacteria.
  • To investigate the mechanism of action of these new compounds, focusing on their effects on bacterial metabolism, cell membranes, and growth.

Main Methods:

  • Synthesis and characterization of alkyl-aryl-vancomycins (AAVs).
  • In vitro testing of AAV potency against vancomycin-resistant enterococci and staphylococci, including methicillin-resistant Staphylococcus aureus (MRSA).
  • Assessment of AAV-qC10's bactericidal activity, metabolic dependence, biofilm disruption, membrane effects, and impact on the MinD protein.
  • In vivo efficacy evaluation of AAV-qC10 in a murine thigh infection model.

Main Results:

  • AAVs demonstrated high potency against vancomycin-resistant enterococci and staphylococci.
  • The lead compound, AAV-qC10, exhibited bactericidal activity, was weakly dependent on bacterial metabolism, and eradicated non-growing MRSA cells.
  • AAV-qC10 disrupted MRSA biofilms and exhibited dual action by inhibiting cell wall biosynthesis and disrupting the bacterial membrane.
  • AAV-qC10 delocalized the MinD protein, impairing bacterial growth through multiple mechanisms.
  • AAV-qC10 showed superior efficacy against MRSA in a murine thigh infection model compared to vancomycin.

Conclusions:

  • Alkyl-aryl-vancomycins represent a promising new class of antibiotics effective against drug-resistant Gram-positive bacteria.
  • AAV-qC10's multifaceted mechanism of action, including targeting biofilms and persister cells, offers a significant advantage over vancomycin.
  • These findings support further development of AAVs for combating challenging bacterial infections and overcoming antibiotic resistance.

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