# Negamycin: Nature’s Forgotten Antibiotic

## TL;DR

Negamycin is a forgotten antibiotic with potential against Gram-negative bacteria, offering a new approach due to its unique mechanism and lack of cross-resistance.

## Contribution

This review highlights recent advancements in understanding negamycin's mechanism and analog development for improved antibacterial activity.

## Key findings

- Negamycin binds to the A-site of the 30S ribosome, inhibiting bacterial protein synthesis.
- Novel analogs of negamycin have been developed with greater potency than the original compound.
- Understanding negamycin's transport mechanism to the bacterial cytoplasm has advanced.

## Abstract

Negamycin is a natural product antibiotic discovered
in 1970 and
shown to have a Gram-negative spectrum of activity. It has served
as the starting point in drug discovery efforts due in large part
to its structural simplicity and novel mode of inhibition of the bacterial
ribosome. It follows that negamycin does not show cross-resistance
with other antibacterial agents that operate on the ribosome, whether
this would be due to target modification, drug efflux, or drug metabolism.
Because of the deficiencies of current drug regimens for the treatment
of infections caused by Gram-negative pathogens, having a new agent
brought to the infectious disease formulary represents a critical
medical need, as has been promoted by the World Health Organization
and other entities. Negamycin has been the subject of over 20 total
syntheses, often highlighting stereoselective chemistry toward installing
its two chiral centers on an acyclic chain. Novel synthetic methodologies
thereby developed can stimulate the synthesis of novel analogs. With
this, progress has been made in devising more potent analogs than
negamycin. Structural work has determined that negamycin binds to
the A-site of the 30S ribosome encounter complex with tRNA. Advancements
have been made to understand the mechanism of transport of negamycin
to the bacterial cytoplasm to enable engagement of the ribosome. This
review surveys much of what has been published around negamycin and
its analogs, including aspects of the biological spectrum of activity
and mode of action as well as limitations that have held back clinical
development.