Structural Modifications, Structure-Activity Relationships, and Total Synthesis Advances in Erythromycin Analogs against Resistant Pathogens

doi:10.6023/cjoc202506020

Abstract

As clinically important and widely used drugs, macrolide antibiotics exhibit broad-spectrum antimicrobial properties and excellent therapeutic efficacy, such as erythromycin, clarithromycin and azithromycin, all of which are essential medicines recommended by the World Health Organization (WHO). However, the emergence of bacterial resistance has significantly reduced their antibacterial efficacy, leaving the treatment of numerous diseases facing a dilemma of no effective drugs available. In particular, macrolide antibiotics, the 3rd-generation telithromycin and the 4th-generation solithromycin included, are difficult to exert therapeutic effects against infectious diseases caused by constitutive erm-carrying Staphylococcus aureus, constitutive erm-carrying Streptococcus pyogenes, and Mycoplasma pneumoniae with A2058 mutation. To overcome the problem of bacterial resistance to macrolide antibiotics and further enhance their antibacterial activity against drug-resistant bacteria, extensive studies have been performed on new structures. Taking the development history of macrolide antibiotics as a chronological framework, the research progress of these drugs against drug-resistant bacteria from 2013 to 2024 is systematically summarized. This study focuses on elaborating the structure-activity relationships of new structures, pharmacokinetic characteristics, and total synthesis strategies of non-natural macrolides, and summarizes the key breakthroughs of 5th-generation macrolide antibiotics in combating bacterial resistance. This review will provide guidance for subsequent drug design, research on resistance mechanisms, and the development of novel antibacterial strategies.

Key words: macrolide, drug resistance, structural modification, structure-activity relationship, total synthesis

Cite this article

Cui Xinyi, Guo Lifan, Ma Congxuan, Li Yun, Liang Jianhua. Structural Modifications, Structure-Activity Relationships, and Total Synthesis Advances in Erythromycin Analogs against Resistant Pathogens[J]. Chinese Journal of Organic Chemistry, 2026, 46(1): 39-73.

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Macrolide	Species	Res/Å	Method	PDB No.	Ref.
Erythromycin	E. coli	3.60	Electron microscopy	5JU8	[25]
Erythromycin	E. coli	3.60	Electron microscopy	5JTE	[25]
Telithromycin	B. subtilis	3.10	Electron microscopy	6HA1	[26]
Telithromycin	E. coli	3.50	Electron microscopy	6HA8	[26]
Erythromycin	Thermus thermophilus	2.85	X-Ray diffraction	6ND6	[27]
Erythromycin	Staphylococcus aureus	2.42	Electron microscopy	6S0X	[28]
Erythromycin	Thermus thermophilus	2.55	X-Ray diffraction	6XHX	[8]
Telithromycin	Thermus thermophilus	2.60	X-Ray diffraction	6XHY	[8]
Erythromycin	E. coli	2.90	Electron microscopy	7NSO	[29]
Erythromycin	E. coli	3.50	Electron microscopy	7NSP	[29]
Telithromycin	E. coli	3.10	Electron microscopy	7NSQ	[29]
Erythromycin	E. coli	3.00	Electron microscopy	7Q4K	[30]
Erythromycin	Thermus thermophilus	2.50	X-Ray diffraction	8FC1	[31]
Erythromycin	Thermus thermophilus	2.45	X-Ray diffraction	8FC4	[31]
Azithromycin	Thermus thermophilus	2.50	X-Ray diffraction	8FC2	[31]
Azithromycin	Thermus thermophilus	2.65	X-Ray diffraction	8FC5	[31]
Telithromycin	Thermus thermophilus	2.35	X-Ray diffraction	8FC6	[31]
Telithromycin	Thermus thermophilus	2.60	X-Ray diffraction	8FC3	[31]
MCX-66	Thermus thermophilus	2.40	X-Ray diffraction	8VTU	[32]
MCX-128	Thermus thermophilus	2.40	X-Ray diffraction	8VTX	[32]
MCX-128	Thermus thermophilus	2.35	X-Ray diffraction	8VTW	[32]
MCX-91	Thermus thermophilus	2.40	X-Ray diffraction	8VTV	[32]
MCX-190	Staphylococcus aureus	2.58	Electron microscopy	8Y38	[23]
MCX-190	Staphylococcus aureus	3.60	Electron microscopy	8Y39	[23]

Macrolide	Species	Res/Å	Method	PDB No.	Ref.
Erythromycin	E. coli	3.60	Electron microscopy	5JU8	[25]
Erythromycin	E. coli	3.60	Electron microscopy	5JTE	[25]
Telithromycin	B. subtilis	3.10	Electron microscopy	6HA1	[26]
Telithromycin	E. coli	3.50	Electron microscopy	6HA8	[26]
Erythromycin	Thermus thermophilus	2.85	X-Ray diffraction	6ND6	[27]
Erythromycin	Staphylococcus aureus	2.42	Electron microscopy	6S0X	[28]
Erythromycin	Thermus thermophilus	2.55	X-Ray diffraction	6XHX	[8]
Telithromycin	Thermus thermophilus	2.60	X-Ray diffraction	6XHY	[8]
Erythromycin	E. coli	2.90	Electron microscopy	7NSO	[29]
Erythromycin	E. coli	3.50	Electron microscopy	7NSP	[29]
Telithromycin	E. coli	3.10	Electron microscopy	7NSQ	[29]
Erythromycin	E. coli	3.00	Electron microscopy	7Q4K	[30]
Erythromycin	Thermus thermophilus	2.50	X-Ray diffraction	8FC1	[31]
Erythromycin	Thermus thermophilus	2.45	X-Ray diffraction	8FC4	[31]
Azithromycin	Thermus thermophilus	2.50	X-Ray diffraction	8FC2	[31]
Azithromycin	Thermus thermophilus	2.65	X-Ray diffraction	8FC5	[31]
Telithromycin	Thermus thermophilus	2.35	X-Ray diffraction	8FC6	[31]
Telithromycin	Thermus thermophilus	2.60	X-Ray diffraction	8FC3	[31]
MCX-66	Thermus thermophilus	2.40	X-Ray diffraction	8VTU	[32]
MCX-128	Thermus thermophilus	2.40	X-Ray diffraction	8VTX	[32]
MCX-128	Thermus thermophilus	2.35	X-Ray diffraction	8VTW	[32]
MCX-91	Thermus thermophilus	2.40	X-Ray diffraction	8VTV	[32]
MCX-190	Staphylococcus aureus	2.58	Electron microscopy	8Y38	[23]
MCX-190	Staphylococcus aureus	3.60	Electron microscopy	8Y39	[23]

Macrolide	Species	Res/Å	Method	PDB No.	Ref.
Carbamolide 4d	Deinococcus radiodurans	3.20	X-Ray diffraction	4IO9	[33]
Carbamolide 4e	Deinococcus radiodurans	3.20	X-Ray diffraction	4IOA	[33]
Carbamolide 4f	Deinococcus radiodurans	3.60	X-Ray diffraction	4IOC	[33]
Erythromycin	E. coli	6.60	Cryo-electron microscopy	3J5L	[34]
Erythromycin	E. coli	3.90	Cryo-electron microscopy	3J7Z	[35]
Telithromycin	Staphylococcus aureus	3.43	X-Ray diffraction	4WF9	[36]
Erythromycin	Deinococcus radiodurans	3.54	X-Ray diffraction	4WFN	[37]
Erythromycin	Staphylococcus aureus	2.30	Electron microscopy	6S0Z	[28]
Clarithromycin	Mycobacterium tuberculosis	3.30	Electron microscopy	7F0D	[38]
Erythromycin	Mycobacterium smegmatis	3.60	Electron microscopy	8XZ3	[39]
MCX-190	Staphylococcus aureus	2.65	CElectron microscopy	8Y36	[23]
MCX-190	Staphylococcus aureus	2.53	Electron microscopy	8Y37	[23]

Macrolide	Species	Res/Å	Method	PDB No.	Ref.
Carbamolide 4d	Deinococcus radiodurans	3.20	X-Ray diffraction	4IO9	[33]
Carbamolide 4e	Deinococcus radiodurans	3.20	X-Ray diffraction	4IOA	[33]
Carbamolide 4f	Deinococcus radiodurans	3.60	X-Ray diffraction	4IOC	[33]
Erythromycin	E. coli	6.60	Cryo-electron microscopy	3J5L	[34]
Erythromycin	E. coli	3.90	Cryo-electron microscopy	3J7Z	[35]
Telithromycin	Staphylococcus aureus	3.43	X-Ray diffraction	4WF9	[36]
Erythromycin	Deinococcus radiodurans	3.54	X-Ray diffraction	4WFN	[37]
Erythromycin	Staphylococcus aureus	2.30	Electron microscopy	6S0Z	[28]
Clarithromycin	Mycobacterium tuberculosis	3.30	Electron microscopy	7F0D	[38]
Erythromycin	Mycobacterium smegmatis	3.60	Electron microscopy	8XZ3	[39]
MCX-190	Staphylococcus aureus	2.65	CElectron microscopy	8Y36	[23]
MCX-190	Staphylococcus aureus	2.53	Electron microscopy	8Y37	[23]

Strain	Resistance phenotypes (genotypes)	MIC/(μg•mL^－1)
Strain	Resistance phenotypes (genotypes)	14	Clarithromycin
Streptococcus pneumoniae BAA1402	M (mef)	0.03	2
Staphylococcus aureus BAA976	M (mef)	0.03	64
Staphylococcus aureus BA977	iMLS (erm)	0.03	>64

抗耐药菌红霉素的结构修饰策略、构效关系及全合成研究进展