Azithromycin Derivatives for Overcoming Antibacterial Resistance: Structural Modification and Structure–Activity Relationships
- 1Chemistry Discipline, Department of Chemical and Earth Sciences, Faculty of Science and Agriculture, University of Fort Hare, Alice 5700, South Africa
- 2Infectious Diseases and Medicinal Plants Research Niche Area, Botany Discipline, Department of Biotechnology and Biological Sciences, Faculty of Science and Agriculture, University of Fort Hare, Alice 5700, South Africa
- 3Department of Chemistry, Physics, and Geosciences, Tarleton State University, Stephenville, TX 76402, USA
Abstract
Antimicrobial resistance has significantly compromised the therapeutic efficacy of many antibiotics, highlighting the need for new agents capable of overcoming bacterial resistance. The discovery of antibiotics in the early 20th century contributed significantly to transforming modern medicine and saved countless lives. However, the alarming increase in antibiotic resistance now threatens these achievements. The misuse and overuse of antibiotics have driven the continuous evolution and adaptation of microorganisms, contributing to this growing global health challenge. Azithromycin (AZM), a widely used macrolide antibiotic with favorable pharmacokinetic properties, is increasingly affected by resistance mechanisms. A number of researchers have therefore designed and developed AZM derivatives with promising antibacterial properties. This review summarizes advances in the structural modification of AZM, focusing on side-chain modification, heterocyclic substitution, molecular hybridization, and their associated structure–activity relationships. Selected derivatives demonstrated enhanced activity against resistant bacterial pathogens compared with AZM, although activity varies according to substituent position, linker structure, and overall molecular properties. Nevertheless, the activity of many AZM derivatives against Gram-negative organisms remains limited, with restricted outer-membrane permeability and inadequate intracellular accumulation representing important barriers to achieving effective antibacterial activity. Overall, the structural modification of AZM represents a promising strategy for developing potential antibacterial agents, but further pharmacological and in vivo studies are required to establish their therapeutic potential.
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BibTeX
@article{ngece2026azithromycin,
title = {{Azithromycin Derivatives for Overcoming Antibacterial Resistance: Structural Modification and Structure–Activity Relationships}},
author = {Kwanele Ngece and Athandwe M. Paca and Lisa V. Buwa-Komoreng and Blessings A. Aderibigbe and Vuyolwethu Khwaza},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27209110},
url = {https://www.mdpi.com/1422-0067/27/20/9110},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Azithromycin Derivatives for Overcoming Antibacterial Resistance: Structural Modification and Structure–Activity Relationships
AU - Kwanele Ngece
AU - Athandwe M. Paca
AU - Lisa V. Buwa-Komoreng
AU - Blessings A. Aderibigbe
AU - Vuyolwethu Khwaza
PY - 2026
DA - 2026/10/01
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27209110
UR - https://www.mdpi.com/1422-0067/27/20/9110
AB - Antimicrobial resistance has significantly compromised the therapeutic efficacy of many antibiotics, highlighting the need for new agents capable of overcoming bacterial resistance. The discovery of antibiotics in the early 20th century contributed significantly to transforming modern medicine and saved countless lives. However, the alarming increase in antibiotic resistance now threatens these achievements. The misuse and overuse of antibiotics have driven the continuous evolution and adaptation of microorganisms, contributing to this growing global health challenge. Azithromycin (AZM), a widely used macrolide antibiotic with favorable pharmacokinetic properties, is increasingly affected by resistance mechanisms. A number of researchers have therefore designed and developed AZM derivatives with promising antibacterial properties. This review summarizes advances in the structural modification of AZM, focusing on side-chain modification, heterocyclic substitution, molecular hybridization, and their associated structure–activity relationships. Selected derivatives demonstrated enhanced activity against resistant bacterial pathogens compared with AZM, although activity varies according to substituent position, linker structure, and overall molecular properties. Nevertheless, the activity of many AZM derivatives against Gram-negative organisms remains limited, with restricted outer-membrane permeability and inadequate intracellular accumulation representing important barriers to achieving effective antibacterial activity. Overall, the structural modification of AZM represents a promising strategy for developing potential antibacterial agents, but further pharmacological and in vivo studies are required to establish their therapeutic potential.
SN - 1422-0067
ER -