Aggregation into colonies and biofilms can protect bacteria from antibiotic treatment. Treatment of biofilm-related infections requires a detailed understanding of the molecular mechanisms of antibiotic tolerance. This project aims at understanding how colony formation protects the human pathogen Neisseria gonorrhoeae from antibiotic treatment. We will focus on the interplay between the physical properties of gonococcal colonies and antibiotic susceptibility.

We will study the effect of colony formation and colony fluidity on tolerance.
To identify molecular mechanisms that confer antibiotic tolerance, we will follow two complementary approaches.
We will investigate how colony formation affects genome-wide gene expression and correlate differential gene expression to tolerance.
We will study the evolution of antibiotic tolerance.
In the long term, it will be interesting to investigate the interplay between antibiotic tolerance and antibiotic resistance in the gonococcal system.

Figure 1

Fig. 1: Image analysis of colonies formed by N. gonorrhoeae. Gonococci form densely packed spherical colonies. Image analysis tools with single cell resolution unravel effects of antibiotic treatment on colony structure and dynamics. Upper image: Confocal slice through the center of the colony with living (green) and dead (red) cells. Lower image: 3D reconstruction of single cell positions. (adapted from Cronenberg et al 2021)

Clinical Relevance

According to WHO, gonorrhea is currently the second most common STI worldwide. Vaccination is not available and the probability of failure of treatment with antibiotics is rising rapidly (1). Due to its rapid acquisition of antibiotic resistance, (multi-) drug resistant N. gonorrhoeae have been termed an urgent threat by the US Center for Disease Control. Some aspects of drug resistance are understood at the genetic level, but the effect of biofilm formation and its properties on efficiency of treatment remains poorly understood. This project aims at elucidating potential mechanisms of antibiotic tolerance in gonococcal biofilms.

Approach

Characterize the role of colony formation on antibiotic tolerance
Determine changes in gene expression in response to colony formation and correlate them to antibiotic tolerance
Set up laboratory evolution experiment to assess evolution of colony phenotype, tolerance, and resistance

Figure 2

Fig. 2: Linking colony formation to antibiotic tolerance. By generating hybrid strains between clinical isolates and the laboratory strain of N. gonorrhoeae we obtained strains that are inhibited for colony formation. These strains carry different variants of the major subunit of the type 4 pilus (T4P), required for colony formation (Craig et al 2019, Maier 2021). By comparing their killing kinetics (A) with the killing kinetics of colony-forming strains (B), we assess the effect of colony formation on tolerance against antibiotics with different targets.

Craig L, Forest KT, & Maier B (2019) Nat Rev Microbiol. 17(7):429

Maier B (2021) Annual Review of Biophysics, Vol 50, 2021 50:401.

Lab Website

For more information, please check the research website.

Affiliations - Berenike Maier

Affiliations - Paul Higgins

German Center for Infection Research (DZIF)

Publication Record on PubMed - Berenike Maier

Publication Record on PubMed - Paul Higgins

Publications generated during 1/2023-12/2025 with CMMC affiliation

2024 (up to June)

Wannigama DL, Amarasiri M, Phattharapornjaroen P, Hurst C, Modchang C, Chadsuthi S, Anupong S, Miyanaga K, Cui L, Fernandez S, Huang AT, Ounjai P, Singer AC, Ragupathi NKD, Sano D, Furukawa T, Sei K, Leelahavanichkul A, Kanjanabuch T, Chatsuwan T, Higgins PG, Nanbo A, Kicic A, Siow R, Trowsdale S, Hongsing P, Khatib A, Shibuya K, Abe S, Ishikawa H; Pathogen Hunters Research Team. Increased faecal shedding in SARS-CoV-2 variants BA.2.86 and JN.1. Lancet Infect Dis. 2024 Jun;24(6):e348-e350. doi: 10.1016/S1473-3099(24)00155-5. Epub 2024 Mar 21. PMID: 38522445.
Wannigama DL, Amarasiri M, Phattharapornjaroen P, Hurst C, Modchang C, Chadsuthi S, Anupong S, Miyanaga K, Cui L, Werawatte W, Ali Hosseini Rad SM, Fernandez S, Huang AT, Vatanaprasan P, Saethang T, Luk-In S, Storer RJ, Ounjai P, Tacharoenmuang R, Ragupathi NKD, Kanthawee P, Cynthia B, Besa JJV, Leelahavanichkul A, Kanjanabuch T, Higgins PG, Nanbo A, Kicic A, Singer AC, Chatsuwan T, Trowsdale S, Furukawa T, Sei K, Sano D, Ishikawa H, Shibuya K, Khatib A, Abe S, and Hongsing P (2024). Wastewater-based epidemiological surveillance of SARS-CoV-2 new variants BA.2.86 and offspring JN.1 in south and Southeast Asia. J Travel Med. doi:10.1093/jtm/taae040.
Wannigama DL, Hurst C, Phattharapornjaroen P, Hongsing P, Sirichumroonwit N, Chanpiwat K, Rad SMA, Storer RJ, Ounjai P, Kanthawee P, Ngamwongsatit N, Kupwiwat R, Kupwiwat C, Brimson JM, Devanga Ragupathi NK, Charuluxananan S, Leelahavanichkul A, Kanjanabuch T, Higgins PG, Badavath VN, Amarasiri M, Verhasselt V, Kicic A, Chatsuwan T, Pirzada K, Jalali F, Reiersen AM, Abe S, Ishikawa H, and Team CO-ET (2024). Early treatment with fluvoxamine, bromhexine, cyproheptadine, and niclosamide to prevent clinical deterioration in patients with symptomatic COVID-19: a randomized clinical trial. EClinicalMedicine70, 102517. doi:10.1016/j.eclinm.2024.102517.

2023

Forster M, Rathmann I, Yuksel M, Power JJ, and Maier B (2023). Genome-wide transformation reveals extensive exchange across closely related Bacillus species. Nucleic Acids Res 51, 12352-12366. doi:10.1093/nar/gkad1074.
Hennes M, Bender N, Cronenberg T, Welker A, and Maier B (2023). Collective polarization dynamics in bacterial colonies signify the occurrence of distinct subpopulations. PLoS Biol 21, e3001960. doi:10.1371/journal.pbio.3001960.

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