A trimethoprim derivative impedes antibiotic resistance evolution

Area of Science:

• Microbiology
• Drug Discovery
• Evolutionary Biology

Background:

• Trimethoprim (TMP) is a key antibiotic for treating *Escherichia coli* infections.
• Rapid emergence of TMP-resistant bacteria limits its clinical efficacy.
• Specific mutations in dihydrofolate reductase (DHFR), like L28R, confer TMP resistance.

Purpose of the Study:

• To investigate the efficacy of 4"-desmethyltrimethoprim (4"-DTMP) against TMP-resistant *E. coli*.
• To understand how 4"-DTMP modulates bacterial resistance evolution.
• To explore strategies for enhancing long-term antimicrobial therapy effectiveness.

Main Methods:

• Laboratory evolution experiments with *E. coli*.
• In vitro inhibition assays of DHFR and its L28R variant by 4"-DTMP.
• Comparative growth studies of bacterial populations in the presence of TMP and 4"-DTMP.

Main Results:

• 4"-DTMP inhibits both wild-type DHFR and the L28R resistant variant.
• 4"-DTMP selects against *E. coli* acquiring the L28R mutation.
• Bacterial populations exposed to 4"-DTMP exhibit a significantly slower rate of resistance acquisition compared to those exposed to TMP.
• 4"-DTMP diverts evolutionary pathways, favoring DHFR mutations with catalytic deficiencies.

Conclusions:

• 4"-DTMP is a promising candidate for combating TMP-resistant *E. coli* infections.
• Understanding resistance mutations can guide the development of novel antibiotics.
• Modulating bacterial evolutionary trajectories is a viable strategy to prolong antibiotic efficacy.