The activity, mode of action and generation of resistance to novel antibacterial agents

The failure of antibiotics to treat infections caused by multi-drug resistant bacteria is a
significant problem in the field of antimicrobial chemotherapy. The characterisation and
development of antibacterial agents displaying novel modes of action (MOAs) or the
modification of existing antibiotic scaffolds may address this problem. This study
therefore sought to identify antibiotic candidates, establishing their antibacterial
activity, bacterial specificity, MOA and propensity for resistance development. From
nearly half a million compounds which were screened in silica against RNA polymerase
(RNAP), D-alanine: D-alanine ligase and peptidoglycan transglycosylases, no inhibitors
with specific activity against their target were identified, which highlights the
difficulties of developing novel antibacterial agents. However, targeted inhibition of the
cell envelope and RNAP were observed for the type B lantibiotic derivative NVB353
and corallopyronin A, respectively. The former may show greater promise as a
chemotherapeutic candidate, due to lower propensity for resistance development. In
addition, a number of compounds which appear to damage the bacterial cell membrane
specifically were identified, and which may be suitable for treatment of persistent
bacterial infections. Transcriptional profiling of Staphylococcus aureus treated with a
panel of known membrane damagers was also used to identify upregulafed genes which
might be potential candidates for future development of biosensors solely responsive to
membrane damage. These biosensors could be used to eliminate compounds which are
likely to cause non-specific toxic side effects if administered to humans, but may also
identify membrane damaging agents that could be developed for clinical use should
they show bacterial specificity.