Related Experiment Video

Updated: Jun 16, 2026

Nanomechanics of Drug-target Interactions and Antibacterial Resistance Detection
11:56

Nanomechanics of Drug-target Interactions and Antibacterial Resistance Detection

Published on: October 25, 2013

Genetically engineered lipopeptide antibiotics related to A54145 and daptomycin with improved properties

Kien T Nguyen1, Xiaowei He, Dylan C Alexander

  • 1Cubist Pharmaceuticals, Inc., Lexington, Massachusetts 02421, USA.

Antimicrobial Agents and Chemotherapy
|January 21, 2010
PubMed

Insights

Researchers engineered hybrid lipopeptides based on A54145 to combat Gram-positive bacterial infections. One novel compound demonstrated high activity against Staphylococcus aureus and efficacy in a pneumonia model, even with pulmonary surfactant present.

Area of Science:

  • Microbiology
  • Medicinal Chemistry
  • Drug Discovery

Background:

  • Daptomycin is an antibiotic for Gram-positive infections but ineffective for pneumonia due to surfactant interaction.
  • Existing daptomycin analogues show limited improvement in activity against surfactant-affected pathogens.

Purpose of the Study:

  • To develop novel lipopeptide analogues with improved activity in the presence of pulmonary surfactant.
  • To investigate the antibacterial efficacy of hybrid A54145 molecules against Gram-positive pathogens, including Staphylococcus aureus.

Main Methods:

  • Genetic engineering of hybrid A54145 nonribosomal peptide synthetase (NRPS) biosynthetic genes.
  • Expression of engineered genes in Streptomyces fradiae with deletion of the lptI methyltransferase gene.
  • Testing antibacterial activity of generated compounds in the presence of bovine surfactant and in a mouse model of pulmonary infection.

Main Results:

  • Several hybrid A54145 compounds exhibited potent activity against Staphylococcus aureus and other Gram-positive pathogens.
  • One hybrid molecule showed significant activity in the presence of bovine surfactant and low acute toxicity.
  • This compound demonstrated efficacy against Streptococcus pneumoniae in a mouse model of pulmonary infection.

Conclusions:

  • Hybrid lipopeptide engineering is a viable strategy to overcome surfactant-related drug inactivation.
  • The novel A54145 analogue shows promise as a therapeutic agent for Gram-positive bacterial infections, including pneumonia.

More Related Videos

Antimicrobial Peptides Produced by Selective Pressure Incorporation of Non-canonical Amino Acids11:56

Antimicrobial Peptides Produced by Selective Pressure Incorporation of Non-canonical Amino Acids

Published on: May 4, 2018

Generating Transposon Insertion Libraries in Gram-Negative Bacteria for High-Throughput Sequencing08:19

Generating Transposon Insertion Libraries in Gram-Negative Bacteria for High-Throughput Sequencing

Published on: July 7, 2020

Related Concept Videos

Inhibitors of Gram-positive Cell Wall Synthesis01:23

Inhibitors of Gram-positive Cell Wall Synthesis

Bacterial cell walls are typically rigid structures composed mainly of peptidoglycan, a mesh-like polymer that provides mechanical strength and maintains cell shape. The synthesis of peptidoglycan is a crucial process in bacterial growth and serves as a primary target for many antibiotics.Mechanism of Action of Beta-Lactam AntibioticsBeta-lactam antibiotics, such as penicillin, inhibit peptidoglycan synthesis in actively growing cells. These antibiotics share a characteristic four-membered...
Clinical Significance of Antibiotic Resistance01:25

Clinical Significance of Antibiotic Resistance

Methicillin-resistant Staphylococcus aureus (MRSA) presents a critical public health threat, arising from its capacity to resist β-lactam antibiotics due to acquisition of the mecA gene within the staphylococcal cassette chromosome mec (SCCmec). This gene encodes penicillin-binding protein 2a (PBP2a), which impairs binding efficacy of methicillin and other β-lactams. MRSA has evolved into distinct clonal lineages impacting humans and animals alike, reinforcing its significance within the One...
Inhibitors of Bacterial Protein Synthesis01:25

Inhibitors of Bacterial Protein Synthesis

Aminoglycosides constitute a highly potent class of bactericidal antibiotics that exert their antimicrobial effects by targeting the bacterial ribosome, specifically disrupting protein synthesis. These polycationic molecules consist of amino-modified sugars linked via glycosidic bonds to an aminocyclitol core such as 2-deoxystreptamine or streptamine. Their strong positive charges facilitate tight binding to the negatively charged phosphate backbone of ribosomal RNA (rRNA), primarily at the 16S...
Mechanism of Antibiotic Resistance in MRSA01:25

Mechanism of Antibiotic Resistance in MRSA

Antibiotic resistance in bacteria arises when microorganisms evolve the ability to withstand drugs designed to kill them or inhibit their growth, rendering once-effective treatments useless. This phenomenon, driven by genetic change and selection under antibiotic exposure, poses a profound threat to modern medicine. Mechanisms include drug-inactivating enzymes (e.g., β-lactamases), efflux pumps that eject antibiotics, mutations altering antibiotic targets, decreased drug uptake, and acquisition...
Production of Pharmaceuticals01:30

Production of Pharmaceuticals

Industrial insulin production uses genetically engineered E. coli expressing a proinsulin gene controlled by a tryptophan promoter and containing a methionine linker for later cleavage. The cells also carry ampicillin resistance for selective growth. Seed cultures are stored at −80 °C and production begins by thawing a small amount to inoculate starter cultures, which are progressively scaled to a 50,000-L bioreactor. In the bioreactor, E. coli grow in nutrient-rich media under sterile, tightly...
Antimicrobial Proteins01:23

Antimicrobial Proteins

Antimicrobial proteins are important components of the immune system. They aid the body in combating pathogens by either killing them directly or hindering their replication processes. Four main types of antimicrobial substances are interferons, the complement system, iron-binding proteins, and antimicrobial proteins.
Interferons
Interferons (IFNs) are proteins produced by lymphocytes, macrophages, and fibroblasts infected with viruses. While IFNs cannot prevent viruses from entering and...