The outbreak of antibiotic-resistant bacteria, or "superbugs", poses a global public health hazard due to their resilience against the most effective last-line antibiotics. Identifying potent antibacterial agents capable of evading bacterial resistance mechanisms represents the ultimate defense strategy. This study shows that -the otherwise essential micronutrient- manganese turns into a broad-spectrum potent antibiotic when coordinated with a carboxylated nitrogen-doped graphene. This antibiotic material (termed NGA-Mn) not only inhibits the growth of a wide spectrum of multidrug-resistant bacteria but also heals wounds infected by bacteria in vivo and, most importantly, effectively evades bacterial resistance development. NGA-Mn exhibits up to 25-fold higher cytocompatibility to human cells than its minimum bacterial inhibitory concentration, demonstrating its potential as a next-generation antibacterial agent. Experimental findings suggest that NGA-Mn acts on the outer side of the bacterial cell membrane via a multimolecular collective binding, blocking vital functions in both Gram-positive and Gram-negative bacteria. The results underscore the potential of single-atom engineering toward potent antibiotics, offering simultaneously a long-sought solution for evading drug resistance development while being cytocompatible to human cells.

Department of Microbiology Faculty of Medicine and Dentistry Palacký University Olomouc Hněvotínská 3 Olomouc 779 00 Czech Republic

Department of Physical Chemistry Faculty of Science Palacký University Olomouc 17 listopadu 1192 12 Olomouc 771 46 Czech Republic

IT4Innovations VŠB Technical University of Ostrava 17 listopadu 2172 15 Ostrava Poruba 708 00 Czech Republic

Jiangsu Co Innovation Center of Efficient Processing and Utilization of Forest Resources International Innovation Center for Forest Chemicals and Materials College of Chemical Engineering Nanjing Forestry University Longpan Road 159 Nanjing 210037 P R China

Nanotechnology Centre Centre for Energy and Environmental Technologies VŠB Technical University of Ostrava 17 listopadu 2172 15 Ostrava Poruba 708 00 Czech Republic

Regional Centre of Advanced Technologies and Materials Czech Advanced Technology and Research Institute Palacký University Olomouc Šlechtitelů 241 27 Olomouc Holice 783 71 Czech Republic

Shanghai Synchrotron Radiation Facility Shanghai Advanced Research Institute Chinese Academy of Sciences Shanghai 201204 P R China

State Key Laboratory of Radiation Medicine and Protection School for Radiological and Interdisciplinary Sciences Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions Suzhou Medical College Soochow University Suzhou Jiangsu 215123 P R China

Zobrazit více v PubMed

O'Meara S., Nature 2020, 586, S49. PubMed

Roope L. S. J., Smith R. D., Pouwels K. B., Buchanan J., Abel L., Eibich P., Butler C. C., Tan P. S., Walker A. S., Robotham J. V., Wordsworth S., Science 2019, 364, eaau4679. PubMed

Murray J., et al., The Lancet 2022, 399, 629.

Willyard C., Nature 2017, 543, 15. PubMed

Baker S., Science 2015, 347, 1064. PubMed

Gilbert N., Nature 2018, 555, S5. PubMed

Smith P. A., Koehler M. F. T., Girgis H. S., Yan D., Chen Y., Chen Y., Crawford J. J., Durk M. R., Higuchi R. I., Kang J., Murray J., Paraselli P., Park S., Phung W., Quinn J. G., Roberts T. C., Rougé L., Schwarz J. B., Skippington E., Wai J., Xu M., Yu Z., Zhang H., Tan M.‐W., Heise C. E., Nature 2018, 561, 189. PubMed

Wang Z., Koirala B., Hernandez Y., Zimmerman M., Park S., Perlin D. S., Brady S. F., Nature 2022, 601, 606. PubMed PMC

Lazzaro B. P., Zasloff M., Rolff J., Science 2020, 368, eaau5480. PubMed PMC

Wang Z., Koirala B., Hernandez Y., Zimmerman M., Brady S. F., Science 2022, 376, 991. PubMed PMC

Mourtada R., Herce H. D., Yin D. J., Moroco J. A., Wales T. E., Engen J. R., Walensky L. D., Nat. Biotechnol. 2019, 37, 1186. PubMed PMC

Wang Y., Yang Y., Shi Y., Song H., Yu C., Adv. Mater. 2020, 32, 1904106. PubMed

Zhao Y., Guo Q., Dai X., Wei X., Yu Y., Chen X., Li C., Cao Z., Zhang X., Adv. Mater. 2019, 31, 1806024. PubMed PMC

Levy S. B., Marshall B., Nat. Med. 2004, 10, S122. PubMed

Makabenta J. M. V., Nabawy A., Li C.‐H., Schmidt‐Malan S., Patel R., Rotello V. M., Nat. Rev. Microbiol. 2021, 19, 23. PubMed PMC

Hu Z., Zhang C., Sifuentes‐Dominguez L., Zarek C. M., Propheter D. C., Kuang Z., Wang Y., Pendse M., Ruhn K. A., Hassell B., Behrendt C. L., Zhang B., Raj P., Harris‐Tryon T. A., Reese T. A., Hooper L. V., Science 2021, 374, eabe6723. PubMed PMC

Durand‐Reville T. F., Miller A. A., O'Donnell J. P., Wu X., Sylvester M. A., Guler S., Iyer R., Shapiro A. B., Carter N. M., Velez‐Vega C., Moussa S. H., McLeod S. M., Chen A., Tanudra A. M., Zhang J., Comita‐Prevoir J., Romero J. A., Huynh H., Ferguson A. D., Horanyi P. S., Mayclin S. J., Heine H. S., Drusano G. L., Cummings J. E., Slayden R. A., Tommasi R. A., Nature 2021, 597, 698. PubMed

Walsh C., Nature 2000, 406, 775. PubMed

Craney A., Dix M. M., Adhikary R., Cravatt B. F., Romesberg F. E., mBio 2015, 6, e01178. PubMed PMC

Darby E. M., Trampari E., Siasat P., Gaya M. S., Alav I., Webber M. A., Blair J. M. A., Nat. Rev. Microbiol. 2023, 21, 280. PubMed

Lemire J. A., Harrison J. J., Turner R. J., Nat. Rev. Microbiol. 2013, 11, 371. PubMed

Harrison J. J., Ceri H., Turner R. J., Nat. Rev. Microbiol. 2007, 5, 928. PubMed

Li J., Li Z., Liu X., Li C., Zheng Y., Yeung K. W. K., Cui Z., Liang Y., Zhu S., Hu W., Qi Y., Zhang T., Wang X., Wu S., Nat. Commun. 2021, 12, 1224. PubMed PMC

Stabryla L. M., Johnston K. A., Diemler N. A., Cooper V. S., Millstone J. E., Haig S.‐J., Gilbertson L. M., Nat. Nanotechnol. 2021, 16, 996. PubMed

Tu Y., Lv M., Xiu P., Huynh T., Zhang M., Castelli M., Liu Z., Huang Q., Fan C., Fang H., Zhou R., Nat. Nanotechnol. 2013, 8, 594. PubMed

Tu Y., Li P., Sun J., Jiang J., Dai F., Li C., Wu Y., Chen L., Shi G., Tan Y., Fang H., Adv. Funct. Mater. 2021, 31, 2008018.

Xin Q., Shah H., Nawaz A., Xie W., Akram M. Z., Batool A., Tian L., Jan S. U., Boddula R., Guo B., Liu Q., Gong J. R., Adv. Mater. 2019, 31, 1804838. PubMed

Wang G., Feng H., Hu L., Jin W., Hao Q., Gao A., Peng X., Li W., Wong K.‐Y., Wang H., Li Z., Chu P. K., Nat. Commun. 2018, 9, 2055. PubMed PMC

Frei A., Verderosa A. D., Elliott A. G., Zuegg J., Blaskovich M. A. T., Nat. Rev. Chem. 2023. PubMed PMC

Peddinti B. S. T., Scholle F., Vargas M. G., Smith S. D., Ghiladi R. A., Spontak R. J., Mater. Horiz. 2019, 6, 2056.

Li X., Bai H., Yang Y., Yoon J., Wang S., Zhang X., Adv. Mater. 2019, 31, 1805092. PubMed

Santos A. L., Liu D., Reed A. K., Wyderka A. M., van Venrooy A., Li J. T., Li V. D., Misiura M., Samoylova O., Beckham J. L., Ayala‐Orozco C., Kolomeisky A. B., Alemany L. B., Oliver A., Tegos G. P., Tour J. M., Sci. Adv. 2022, 8, eabm2055. PubMed PMC

Zou X., Zhang L., Wang Z., Luo Y., J. Am. Chem. Soc. 2016, 138, 2064. PubMed

Hegab H. M., ElMekawy A., Zou L., Mulcahy D., Saint C. P., Ginic‐Markovic M., Carbon 2016, 105, 362.

Perreault F., de Faria A. F., Nejati S., Elimelech M., ACS Nano 2015, 9, 7226. PubMed

Barbolina I., Woods C. R., Lozano N., Kostarelos K., Novoselov K. S., Roberts I. S., 2D Mater. 2016, 3, 025025.

Panáček D., Hochvaldová L., Bakandritsos A., Malina T., Langer M., Belza J., Martincová J., Večeřová R., Lazar P., Poláková K., Kolařík J., Válková L., Kolář M., Otyepka M., Panáček A., Zbořil R., Adv. Sci. 2021, 8, 2003090. PubMed PMC

Panáček A., Kvítek L., Smékalová M., Večeřová R., Kolář M., Röderová M., Dyčka F., Šebela M., Prucek R., Tomanec O., Zbořil R., Nat. Nanotechnol. 2018, 13, 65. PubMed

Zabara M., Senturk B., Gontsarik M., Ren Q., Rottmar M., Maniura‐Weber K., Mezzenga R., Bolisetty S., Salentinig S., Adv. Funct. Mater. 2019, 29, 1904007.

Cai T., Fang G., Tian X., Yin J.‐J., Chen C., Ge C., ACS Nano 2019, 13, 12694. PubMed

Wang A., Li J., Zhang T., Nat. Rev. Chem. 2018, 2, 65.

Liang Z., Shen J., Xu X., Li F., Liu J., Yuan B., Yu Y., Zhu M., Adv. Mater. 2022, 34, 2200102. PubMed

Wang Y., Chu F., Zeng J., Wang Q., Naren T., Li Y., Cheng Y., Lei Y., Wu F., ACS Nano 2021, 15, 210. PubMed

Qian J., Dong Q., Chun K., Zhu D., Zhang X., Mao Y., Culver J. N., Tai S., German J. R., Dean D. P., Miller J. T., Wang L., Wu T., Li T., Brozena A. H., Briber R. M., Milton D. K., Bentley W. E., Hu L., Nat. Nanotechnol. 2022, 1. PubMed

Wang L., Yang Q., Huo M., Lu D., Gao Y., Chen Y., Xu H., Adv. Mater. 2021, 33, 2100150. PubMed

Xia C., Qiu Y., Xia Y., Zhu P., King G., Zhang X., Wu Z., Yoon (Timothy) Kim J., Cullen D. A., Zheng D., Li P., Shakouri M., Heredia E., Cui P., Alshareef H. N., Hu Y., Wang H., Nat. Chem. 2021, 13, 887. PubMed

Georgakilas V., Perman J. A., Tucek J., Zboril R., Chem. Rev. 2015, 115, 4744. PubMed

Qi K., Chhowalla M., Voiry D., Mater. Today 2020, 40, 173.

Ha M., Kim D. Y., Umer M., Gladkikh V., Myung C. W., Kim K. S., Energy Environ. Sci. 2021, 14, 3455.

Fei H., Dong J., Feng Y., Allen C. S., Wan C., Volosskiy B., Li M., Zhao Z., Wang Y., Sun H., An P., Chen W., Guo Z., Lee C., Chen D., Shakir I., Liu M., Hu T., Li Y., Kirkland A. I., Duan X., Huang Y., Nat. Catal. 2018, 1, 63.

Long Y., Li L., Xu T., Wu X., Gao Y., Huang J., He C., Ma T., Ma L., Cheng C., Zhao C., Nat. Commun. 2021, 12, 6143. PubMed PMC

Huang L., Chen J., Gan L., Wang J., Dong S., Sci. Adv. 2019, 5, eaav5490. PubMed PMC

Xu B., Wang H., Wang W., Gao L., Li S., Pan X., Wang H., Yang H., Meng X., Wu Q., Zheng L., Chen S., Shi X., Fan K., Yan X., Liu H., Angew. Chem. 2019, 131, 4965.

Jiang K., Back S., Akey A. J., Xia C., Hu Y., Liang W., Schaak D., Stavitski E., Nørskov J. K., Siahrostami S., Wang H., Nat. Commun. 2019, 10, 3997. PubMed PMC

Yang Y., Sun J., Wen J., Mo S., Wang J., Zhang Z., Wang G., Liu M., Liu H., Cell Rep. Phys. Sci. 2021, 2, 100535.

Li J., Liu X., Tan L., Cui Z., Yang X., Liang Y., Li Z., Zhu S., Zheng Y., Yeung K. W. K., Wang X., Wu S., Nat. Commun. 2019, 10, 4490. PubMed PMC

Panáček D., Zdražil L., Langer M., Šedajová V., Baďura Z., Zoppellaro G., Yang Q., Nguyen E. P., Álvarez‐Diduk R., Hrubý V., Kolařík J., Chalmpes N., Bourlinos A. B., Zbořil R., Merkoçi A., Bakandritsos A., Otyepka M., Small 2022, 31, 2201003. PubMed

Ilton E. S., Post J. E., Heaney P. J., Ling F. T., Kerisit S. N., Appl. Surf. Sci. 2016, 366, 475.

Kolařík J., Bakandritsos A., Bad'ura Z., Lo R., Zoppellaro G., Kment Š., Naldoni A., Zhang Y., Petr M., Tomanec O., Filip J., Otyepka M., Hobza P., Zbořil R., ACS Nano 2021, 15, 3349. PubMed

Kim W., Zhu W., Hendricks G. L., Van Tyne D., Steele A. D., Keohane C. E., Fricke N., Conery A. L., Shen S., Pan W., Lee K., Rajamuthiah R., Fuchs B. B., Vlahovska P. M., Wuest W. M., Gilmore M. S., Gao H., Ausubel F. M., Mylonakis E., Nature 2018, 556, 103. PubMed PMC

Ling L. L., Schneider T., Peoples A. J., Spoering A. L., Engels I., Conlon B. P., Mueller A., Schäberle T. F., Hughes D. E., Epstein S., Jones M., Lazarides L., Steadman V. A., Cohen D. R., Felix C. R., Fetterman K. A., Millett W. P., Nitti A. G., Zullo A. M., Chen C., Lewis K., Nature 2015, 517, 455. PubMed PMC

Li Y., Liu X., Tan L., Cui Z., Yang X., Zheng Y., Yeung K. W. K., Chu P. K., Wu S., Adv. Funct. Mater. 2018, 28, 1800299.

Feng X., Lei J., Ma L., Ouyang Q., Zeng Y., Liang H., Lei C., Li G., Tan L., Liu X., Yang C., Small 2022, 18, 2105775. PubMed

Gracioso L. H., Peña‐Bahamonde J., Karolski B., Borrego B. B., Perpetuo E. A., do Nascimento C. A. O., Hashiguchi H., Juliano M. A., Robles Hernandez F. C., Rodrigues D. F., Sci. Adv. 2021, 7, eabd9210. PubMed PMC

Wang X., Shi Q., Zha Z., Zhu D., Zheng L., Shi L., Wei X., Lian L., Wu K., Cheng L., Bioact. Mater. 2021, 6, 4389. PubMed PMC

Malina T., Hirsch C., Rippl A., Panacek D., Polakova K., Sedajova V., Scheibe M., Zboril R., Wick P., Carbon 2023, 211, 118093.

Bhattacharya K., Mukherjee S. P., Gallud A., Burkert S. C., Bistarelli S., Bellucci S., Bottini M., Star A., Fadeel B., Nanomed. Nanotechnol. Biol. Med. 2016, 12, 333. PubMed PMC

Jorge de Souza T. A., Rosa Souza L. R., Franchi L. P., Ecotoxicol. Environ. Saf. 2019, 171, 691. PubMed

Panda S., Rout T. K., Prusty A. D., Ajayan P. M., Nayak S., Adv. Mater. 2018, 30, 1702149. PubMed

EUCAST‐MIC determination, can be found under: http://www.eucast.org/ast_of_bacteria/mic_determination/?no_cache=1 (accessed: September 2024).

Shukla R., Lavore F., Maity S., Derks M. G. N., Jones C. R., Vermeulen B. J. A., Melcrová A., Morris M. A., Becker L. M., Wang X., Kumar R., Medeiros‐Silva J., van Beekveld R. A. M., Bonvin A. M. J. J., Lorent J. H., Lelli M., Nowick J. S., MacGillavry H. D., Peoples A. J., Spoering A. L., Ling L. L., Hughes D. E., Roos W. H., Breukink E., Lewis K., Weingarth M., Nature 2022, 608, 390. PubMed PMC

Liu S., Zeng T. H., Hofmann M., Burcombe E., Wei J., Jiang R., Kong J., Chen Y., ACS Nano 2011, 5, 6971. PubMed

Mukherjee S. P., Gupta G., Klöditz K., Wang J., Rodrigues A. F., Kostarelos K., Fadeel B., Small 2020, 16, 1907686. PubMed

Gao M., Xu B., Huang Y., Cao J., Yang L., Liu X., Djumaev A., Wu D., Shoxiddinova M., Cai X., Tojiyev B., Zheng H., Li X., Normurodova K., Liu H., Li R., Angew. Chem. 2023, 135, e202305485. PubMed

Pan Y., Zheng H., Li G., Li Y., Jiang J., Chen J., Xie Q., Wu D., Ma R., Liu X., Xu S., Jiang J., Cai X., Gao M., Wang W., Zuilhof H., Ye M., Li R., ACS Nano 2022, 16, 7674. PubMed