Antibacterial activity of novel linear polyamines against Staphylococcus aureus

• Published in: Frontiers in microbiology Vol. 13; p. 948343
• Main Authors: Douglas, Edward J. A., Alkhzem, Abdulaziz H., Wonfor, Toska, Li, Shuxian, Woodman, Timothy J., Blagbrough, Ian S., Laabei, Maisem
• Format: Journal Article
• Language: English
• Published: Frontiers Media S.A 22-08-2022
• Subjects: antibacterial activity; antibiotic synergy; antimicrobial resistance (AMR); Microbiology; polyamines; Staphylococcus aureus
• ISSN: 1664-302X; 1664-302X
• DOI: 10.3389/fmicb.2022.948343

New therapeutic options are urgently required for the treatment of
Staphylococcus aureus
infections. Accordingly, we sought to exploit the vulnerability of
S. aureus
to naturally occurring polyamines. We have developed and tested the anti-staphylococcal activity of three novel linear polyamines based on spermine and norspermine. Using a panel of genetically distinct and clinically relevant multidrug resistant
S. aureus
isolates, including the polyamine resistant USA300 strain LAC, compound AHA-1394 showed a greater than 128-fold increase in inhibition against specific
S. aureus
strains compared to the most active natural polyamine. Furthermore, we show that AHA-1394 has superior biofilm prevention and biofilm dispersal properties compared to natural polyamines while maintaining minimal toxicity toward human HepG2 cells. We examined the potential of
S. aureus
to gain resistance to AHA-1394 following
in vitro
serial passage. Whole genome sequencing of two stable resistant mutants identified a gain of function mutation (S337L) in the phosphatidylglycerol lysyltransferase
mprF
gene. Inactivation of mutant
mprF
confirmed the importance of this allele to AHA-1394 resistance. Importantly, AHA-1394 resistant mutants showed a marked decrease in relative fitness and increased generation time. Intriguingly,
mprF
::S337L contributed to altered surface charge only in the USA300 background whereas increased cell wall thickness was observed in both USA300 and SH1000. Lastly, we show that AHA-1394 displays a particular proclivity for antibiotic potentiation, restoring sensitivity of MRSA and VRSA isolates to daptomycin, oxacillin and vancomycin. Together this study shows that polyamine derivatives are impressive drug candidates that warrant further investigation.