Abstract
Due to the inexorable invasion of our hospitals and communities by drug-resistant bacteria, there is a pressing need for novel antibacterial agents. Here we report the development of a sensitive and robust but low-tech and inexpensive high-throughput metabolic screen for novel antibiotics. This screen is based on a colorimetric assay of pH that identifies inhibitors of bacterial sugar fermentation. After validation of the method, we screened over 39,000 crude extracts derived from organisms that grow in the diverse ecosystems of Costa Rica and identified 49 with reproducible antibacterial effects. An extract from an endophytic fungus was further characterized, and this led to the discovery of three novel natural products. One of these, which we named mirandamycin, has broad-spectrum antibacterial activity against Escherichia coli, Pseudomonas aeruginosa, Vibrio cholerae, methicillin-resistant Staphylococcus aureus, and Mycobacterium tuberculosis. This demonstrates the power of simple high throughput screens for rapid identification of new antibacterial agents from environmental samples.
Highlights
Microbes that live together in the environment develop longlasting methods to keep each other at bay
The emergence of bacteria with resistance to multiple antimicrobial agents has motivated the development of high throughput chemical screens (HTS) to identify novel antibiotics
We recently showed that transport of sucrose by V. cholerae depends entirely on a phosphotransfer cascade known as the phosphoenolpyruvate phosphotransferase system or PTS, which regulates biofilm formation [10,19]
Summary
Microbes that live together in the environment develop longlasting methods to keep each other at bay. The emergence of bacteria with resistance to multiple antimicrobial agents has motivated the development of high throughput chemical screens (HTS) to identify novel antibiotics. These screens differ in the number of samples that can reasonably be evaluated and the level of technology required to carry out the screen [4,5,6,7]. The great disadvantage, is that, in secondary screens, the compound is often found to have no activity against intact bacteria due to inadequate penetration, rapid efflux, or inactivation by bacterial products [8] For this reason, compounds discovered in screens using whole cells are often farther along the path to the development of a successful antibacterial agent
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