Searching for new strategies against polymicrobial biofilm infections: guanylated polymethacrylates kill mixed fungal/bacterial biofilms.
OBJECTIVE
Biofilm-related human infections have high mortality rates due to drug resistance. Cohabitation of diverse microbes in polymicrobial biofilms is common and these infections present additional challenges for treatment compared with monomicrobial biofilms. Here, we address this therapeutic gap by assessing the potential of a new class of antimicrobial agents, guanylated polymethacrylates, in the treatment of polymicrobial biofilms built by two prominent human pathogens, the fungus Candida albicans and the bacterium Staphylococcus aureus.


METHODS
We used imaging and quantitative methods to test the antibiofilm efficacy of guanylated polymethacrylates, a new class of drugs that structurally mimic antimicrobial peptides. We further compared guanylated polymethacrylates with first-line antistaphylococcal and anti-Candida agents used as combinatorial therapy against polymicrobial biofilms.


RESULTS
Guanylated polymethacrylates were highly effective as a sole agent, killing both C. albicans and S. aureus when applied to established polymicrobial biofilms. Furthermore, they outperformed multiple combinations of current antimicrobial drugs, with one of the tested compounds killing 99.98% of S. aureus and 82.2% of C. albicans at a concentration of 128 mg/L. The extracellular biofilm matrix provided protection, increasing the MIC of the polymethacrylates by 2-4-fold when added to planktonic assays. Using the C. albicans bgl2ΔΔ mutant, we implicate matrix polysaccharide β-1,3 glucan in the mechanism of protection. Data for two structurally distinct polymers suggest that this mechanism could be minimized through chemical optimization of the polymer structure. Finally, we demonstrate that a potential application for these polymers is in antimicrobial lock therapy.


CONCLUSIONS
Guanylated polymethacrylates are a promising lead for the development of an effective monotherapy against C. albicans/S. aureus polymicrobial biofilms.
Department of Biochemistry and Molecular Biology, Faculty of Medicine, Nursing and Health Science, Monash University, Clayton, VIC 3800, Australia Department of Microbiology, Faculty of Medicine, Nursing and Health Science, Monash University, Clayton, VIC 3800, Australia Department of Infectious Diseases, The Alfred Hospital and Monash University, Melbourne, VIC 3000, Australia.
Yue
Y
Qu
CSIRO Manufacturing Flagship, Clayton, VIC 3168, Australia.
Katherine
K
Locock
Department of Biochemistry and Molecular Biology, Faculty of Medicine, Nursing and Health Science, Monash University, Clayton, VIC 3800, Australia.
Jiyoti
J
Verma-Gaur
Department of Microbiology, Faculty of Medicine, Nursing and Health Science, Monash University, Clayton, VIC 3800, Australia.
Iain D
ID
Hay
CSIRO Manufacturing Flagship, Clayton, VIC 3168, Australia Department of Materials Science and Monash Institute of Medical Engineering, Monash University, Clayton, VIC 3800, Australia.
Laurence
L
Meagher
Department of Biochemistry and Molecular Biology, Faculty of Medicine, Nursing and Health Science, Monash University, Clayton, VIC 3800, Australia ana.traven@monash.edu.
Ana
A
Traven
D000890:Anti-Infective Agents / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects*; D002176:Candida albicans / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D011109:Polymethacrylic Acids / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000502:physiology*
D000890:Anti-Infective Agents; D011109:Polymethacrylic Acids; C030613:polymethacrylic acid