How Combined Macrolide Nanomaterials are Effective Against Resistant Pathogens? A Comprehensive Review of the Literature

Figures & data

Table 1 Some Examples of Multi-Drug Resistant Microbes with Their Mechanism of Resistance

Microorganisms	Mechanism of Resistance	Resistant Drugs	Reference
S. pneumoniae	Modification of the ribosomal target by methylation or mutation and active efflux of the drug	Beta lactams and macrolides	[12]
Viridans and streptococci	Post-transcriptional target site modifications caused by rRNA methylases (erm-class genes); Target mutations (in 23S rRNA or ribosomal proteins L4 and L22); or Acquisition of active efflux (mef genes)	Beta lactams, aminoglycoside, and macrolides	[13]
Streptococcus pyogenes	Mediated by two classes of methylases encoded by erm(B) and erm(TR) genes	Macrolide and penicillins	[14]
Gram positive anaerobes (peptostreptococcus and clostridium species)	Erythromycin-resistant methylase is encoded by erm genes. Resultant structural changes to rRNA prevent macrolide binding and allow synthesis of bacterial proteins to continue.	Penicillins and macrolides	[15]
S. aureus	Target-site modification by methylation or mutation that prevents the binding of the antibiotic to its ribosomal target, Efflux of the antibiotic, and Drug inactivation	Lincosamide, macrolides,	[16]
Group B, C and G streptococci	Production of an additional PBP, designated PBP2a, with a reduction to the drug affinity.	Penicillin, macrolide, and aminoglycoside	[17]
Coagulase-negative staphylococci	Extracellular enzyme, synthesized when staphylococci are exposed to the antibiotics, hydrolyzes the drug structure, rendering it inactive.	Beta lactams, macrolides, aminoglycoside, lincosamide, and glycopeptide	[18]

Figure 1 Multiple resistance mechanism of bacteria to MDR pathogen.

Notes: Reproduced from Imran M, Jha SK, Hasan et al. Overcoming Multidrug Resistance of Antibiotics via Nanodelivery Systems. Pharmaceutics. 2022;14(3):1–25 (https://creativecommons.org/licenses/by/4.0/).¹

Table 2 Parameters That Determine the Pharmaceutical Application of Nanoparticles

Parameters	Factor	Importance	Examples	Reference
Surface area and particle size	Smaller or larger in size	Larger surface area the contact o the NPs to the microorganism Lengthy nanoparticles extend the drug release	Azithromycin loaded with noisomes in combination with levofloxacin showed an increase in contact angle between the NPs and the microbes with increasing surface area and decreasing size	[50,65–67]
Particle shape	Sphere, pyramid, plate	It can determine the basis of wavering degrees of damage to pathogens through periplasmic enzymes	ZnO NPs of various shapes (sphere, pyramid, and plate) exhibit varied photocatalytic activities with β-galactosidase leading to functional and conformational change in the enzyme	[68]
Environmental Condition	pH, Temperature	Affect the antimicrobial potency NPs function beyond optimum temperature and NPs targeting these enzymes would be ineffective with elevated T^0.	Reduced pH shows high dissolution of ZnO NPs and adhesion of NPs on the bacterial membrane of MRSA and E. coli	[69]
Roughness/particle surface	Rougher or smoother surface	It can decrease the adhesion of microbes, as the size and surface area-to-mass ratio stimulate the adsorption of bacterial proteins	Clarithromycin using PGLA-Ag NPs with rougher surface showed improved adsorption of the microbes and better effect.	[65,70]
Zeta potential	Neutral, anions or cations	Resiliently impacts microbial adhesion	Mg(OH)2 NPs, being positively charged are adsorbed on microbial surfaces and this accumulation at the site of infection ascends the permeability	[71]
Doping modifications	n-doping, p-doping	Allow proper dispersal of NPs in hydrophilic or aqueous environments	Cr doping on the ZnO NPs significantly enhanced their antimicrobial activity against a wide range of pathogenic bacteria	[29]

Figure 2 Different mechanisms of action of NPs in bacterial.

Notes: Reproduced from Baptista PV, McCusker MP, Carvalho A, Ferreira DA. Nano-Strategies to Fight Multidrug Resistant Bacteria – “A Battle of the Titans”. Front Microbiol. 2018;9:1–26 (https://creativecommons.org/licenses/by/4.0/).²⁹

Figure 3 Diagrammatic explanation of different Nano carriers.

Notes: Reproduced from Chowdhury A, Kunjiappan S, Panneerselvam T. Nanotechnology and nanocarrier-based approaches on treatment of degenerative diseases. Int Nano Lett. 2017;7(2):91–122 (https://creativecommons.org/licenses/by/4.0/).⁸²

Table 3 Example of Nanomaterials Based Drug Formulation of Various Macrolide Drugs

Drug	Utilized NPs	Outcome	Reference
Clarithromycin	PLGA NPs	Significantly higher mean inhibition zone diameters against S. aureus. The increased potency of CLR NPs may be related to some physicochemical properties of NPs like modified surface characteristics, lower drug degradation, and increased drug adsorption and uptake.	[3]
	CdS/NiO NPs	The loading involved physical complex formation rather than chemical modification with the high percent surface loading of the drugs on the NPs. Significantly higher solubility/dissolution improvement in the solubility of the drug from the NPs	[89]
	LCHNPs	Effectively disrupted biofilm architecture, removed EPS, prevented reformation of biofilm by effectively inhibiting bacterial adhesion and eliminated pathogens. Thus, exhibiting an excellent eradicating ability to H. pylori biofilm.	[81]
	GECM coated PLGA	The affinity of H. pylori with the biomimetic nanocarriers was 10-fold higher than that with non-coated NPs. The bacterial burden in stomach of the infected mice was reduced significantly by oral delivery of the biomimetic nanoparticles.	[82]
	Liposomal NPs	Exhibited enhanced therapeutic effect towards biofilm-forming P. aeruginosa. Enhanced susceptibility than the free drug	[83]
Azithromycin	Gold NPs	Numerous reports suggested that inorganic nanomaterials, specifically gold nanoparticles (AuNPs), have converted unresponsive antibiotics into potent ones against multi-drug resistant pathogenic strains.	[87,91]
	Niosomal Delivery	Mean minimal inhibitory concentration significantly lower than free AZM. More effective against extensively drug-resistant K. pneumoniae	[92]
	Liposomal NPs	Synergized the antibacterial effect of the entrapped AZT. The MIC values of AZT-LPs were marginally lower than those of free AZT.	[27]
	PAMAM-DA NPs	Improved penetration and retention inside biofilms, enhanced permeabilization of the bacterial membrane, and increased internalization of AZM, thus exhibiting excellent anti-biofilm activities. Provided an effective way for the management of biofilm-associated infections, including chronic lung infection.	[88,93]
Erythromycin	SLNPs	Provided desired drug release, protection of drug degradation and resistance, and avoidance of organic solvents.	[94]
	PAMAM Dendrimer	Sustained-release erythromycin delivery. A high drug payload, enhanced solubilization, and resulted in higher activity	[95]
	PCL-PEG micelle	Able to rapidly enter S. aureus and to provide sustained release cargoes Effectively inhibited S. aureus proliferation. A new platform for the rational and effective use of hydrophobic antibiotics to treat infections.	[84,90]
Roxithromycin	PEG-PLGA NPs	Increased bioavailability and decrease resistance to various pathogens	[85]
	Cyclodextrin NCs	Significantly inhibited the Staphylococcus aureus biofilm resulting in bacterial death.	[86]

Abbreviations: GECM, gastric epithelial cell membrane; LCHNPs, lipid-coated hybrid nanoparticles; CdS/NiO NPs, Cadmium sulfide (CdS) and Nickel oxide (NiO) Nanoparticles; PAMAM, poly(amidoamine); NCs, nano Carriers.

Figure 4 General mechanism of action for silver nanoparticles.

Notes: Reproduced from Roy A, Bulut O, Some S, Mandal AK, Yilmaz MD. Green synthesis of silver nanoparticles: biomolecule-nanoparticle organizations targeting antimicrobial activity. RSC Advances. 2019;5:2673–702 (https://creativecommons.org/licenses/by-nc/3.0/).⁸¹

Figure 5 Proposed mechanism of action of AZT-D-LPs.

Notes: Reproduced from Liu X, Li Z, Wang et al. Novel antimicrobial peptide—modified azithromycin-loaded liposomes against methicillin-resistantStaphylococcus aureus. Int J Nanomedicine. 2016;11:6781–94 (https://creativecommons.org/licenses/by-nc/3.0/).⁷³

Baquero F. Gram-positive resistance: challenge for the development of new antibiotics. J Antimicrob Chemother. 1997;39(SUPPL. A):1–6. doi:10.1093/jac/39.suppl_1.1

 PubMed Web of Science ®Google Scholar

Das B, Patra S. Antimicrobials: meeting the challenges of antibiotic resistance through nanotechnology. In: Nanostructures for Antimicrobial Therapy: Nanostructures in Therapeutic Medicine Series. Elsevier Inc.; 2017:1–22.

 Google Scholar

Ergin A, Ercis S, Hasçelik G. Macrolide resistance mechanisms and in vitro susceptibility patterns of viridans group streptococci isolated from blood cultures. J Antimicrob Chemother. 2006;2005:139–141. doi:10.1093/jac/dki404

 Google Scholar

Peche J. Macrolide resistance mechanisms in Gram-positive cocci. Int J Antimicrob Agents. 2001;18:1–4. doi:10.1016/S0924-8579(01)00396-X

 PubMed Web of Science ®Google Scholar

Miklasi M. Mechanisms of resistance to macrolide antibiotics among Staphylococcus aureus. Antibiotics. 2021;2021:1.

 Google Scholar

Jubeh B, Breijyeh Z, Ismail A. Resistance of gram-positive bacteria to current antibacterial agents and overcoming approaches. Molecules. 2020;26:1–22. doi:10.3390/molecules26010001

 PubMedGoogle Scholar

John JF, Harvin AM. History and evolution of antibiotic resistance in coagulase-negative staphylococci: susceptibility pro fi les of new anti-staphylococcal agents. Ther Clin Risk Manag. 2007;3(14):1143–1152.

 PubMedGoogle Scholar

Imran M, Jha SK, Hasan N, et al. Overcoming multidrug resistance of antibiotics via nanodelivery systems. Pharmaceutics. 2022;14(3):1–25. doi:10.3390/pharmaceutics14030586

 Web of Science ®Google Scholar

Brar B, Marwaha S, Poonia AK, Koul B, Kajla S, Rajput VD. Nanotechnology: a contemporary therapeutic approach in combating infections from multidrug-resistant bacteria. Arch Microbiol. 2023;205(2):1–19. doi:10.1007/s00203-023-03404-3

 Web of Science ®Google Scholar

Saddik MS, Elsayed MMA, El-Mokhtar MA, et al. Tailoring of novel azithromycin-loaded zinc oxide nanoparticles for wound healing. Pharmaceutics. 2022;14(1):111. doi:10.3390/pharmaceutics14010111

 PubMed Web of Science ®Google Scholar

Schleh C, Semmler-behnke M, Lipka J, et al. Size and surface charge of gold nanoparticles determine absorption across intestinal barriers and accumulation in secondary target organs after oral administration. Nanotoxicology. 2012;2012:5390.

 Google Scholar

Kalhapure RS, Suleman N, Mocktar C, Seedat N, Govender T. Nanoengineered drug delivery systems for enhancing antibiotic therapy. J Pharm Sci. 2014;2014:1–34.

 Google Scholar

Mitchell MJ, Billingsley MM, Haley RM, Langer R, Wechsler ME, Peppas NA. Engineering precision nanoparticles. Nat Rev Drug Discov. 2021;20:101–124. doi:10.1038/s41573-020-0090-8

 PubMed Web of Science ®Google Scholar

Joseph TM, Mahapatra DK, Esmaeili A, et al. Nanoparticles: taking a unique position in medicine. Nanomaterials. 2023;13:574. doi:10.3390/nano13030574

 Web of Science ®Google Scholar

Baptista PV, McCusker MP, Carvalho A, Ferreira DA. Nano-strategies to fight multidrug resistant bacteria —“a battle of the titans”. Front Microbiol. 2018;9(July):1–26. doi:10.3389/fmicb.2018.01441

 PubMedGoogle Scholar

Chowdhury A, Kunjiappan S, Panneerselvam T. Nanotechnology and nanocarrier-based approaches on treatment of degenerative diseases. Int Nano Lett. 2017;7(2):91–122.

 Web of Science ®Google Scholar

Valizadeh H, Mohammadi G, Ehyaei R, Milani M, Azhdarzadeh M, Lotfipour F. Antibacterial activity of clarithromycin loaded PLGA nanoparticles. Int J Pharm Sci. 2012;2012:63–68.

 Google Scholar

Angsantikul P, Thamphiwatana S, Zhang Q, et al. Coating nanoparticles with gastric epithelial cell membrane for targeted antibiotic delivery against helicobacter pylori infection. Adv Ther. 2018;2018:1–9.

 Google Scholar

Roy A, Bulut O, Some S, Mandal AK, Yilmaz MD. Green synthesis of silver nanoparticles: biomolecule-nanoparticle organizations targeting antimicrobial activity. RSC Adv. 2019;9:2673–2702. doi:10.1039/C8RA08982E

 PubMed Web of Science ®Google Scholar

Dobson J. Magnetic nanoparticles for drug delivery. Drug Dev Res. 2006;67(1):55–60. doi:10.1002/ddr.20067

 Web of Science ®Google Scholar

Bhattacharyya S, Reddy P. Effect of surfactant on azithromycin dihydrate loaded stearic acid solid lipid nanoparticles. Turkish J Pharm Sci. 2019;16(4):425–431. doi:10.4274/tjps.galenos.2018.82160

 PubMed Web of Science ®Google Scholar

Mohd S, Rizvi D, Selim A, et al. Antibiotic-loaded gold nanoparticles: a nano-arsenal against ESBL producer-resistant pathogens. Pharmaceutics. 2023;2023:1–20.

 Google Scholar

Abruzzo A, Parolin C, Rossi M, Vitali B, Cappadone C, Bigucci F. Development and characterization of azithromycin-loaded microemulsions: a promising tool for the treatment of bacterial skin infections. Antibiotics. 2022;11(8):1040. doi:10.3390/antibiotics11081040

 Google Scholar

Koopaei MN, Maghazei MS, Mostafavi SH, et al. Enhanced antibacterial activity of roxithromycin loaded pegylated poly lactide-co-glycolide nanoparticles. J Pharm Sci. 2012;20(1):1–8.

 Google Scholar

Honary S, Zahir F. Effect of zeta potential on the properties of nano-drug delivery systems - a review (part 1). Trop J Pharm Res. 2013;12(April):255–264.

 Google Scholar

Owais HM, Baddour MM, El-metwally HAE, Barakat HS, Ammar NS, Meheissen MA. Assessment of the in vitro activity of azithromycin niosomes alone and in combination with levofloxacin on extensively drug-resistant Klebsiella pneumoniae clinical isolates. Braz J Microbiol. 2021;52:597–606. doi:10.1007/s42770-021-00433-2

 PubMed Web of Science ®Google Scholar

Gao Y, Wang J, Chai M, et al. Size and charge adaptive clustered nanoparticles targeting the bio fi lm microenvironment for chronic lung infection management. ACS nano. 2020;14:5686–5699. doi:10.1021/acsnano.0c00269

 PubMed Web of Science ®Google Scholar

Bosnjakovic A, Mishra MK, Ren W, et al. Poly (amidoamine) dendrimer-erythromycin conjugates for drug delivery to macrophages involved in periprosthetic inflammation. Biol Med. 2011;7(3):284–294. doi:10.1016/j.nano.2010.10.008

 Google Scholar

Li P, Chen X, Shen Y, et al. Mucus penetration enhanced lipid polymer nanoparticles improve the eradication rate of Helicobacter pylori bio fi lm. J Control Release. 2019;300(132):52–63. doi:10.1016/j.jconrel.2019.02.039

 PubMedGoogle Scholar

Alhajlan M, Alhariri M, Omri A. Efficacy and safety of liposomal clarithromycin and its effect on pseudomonas aeruginosa virulence factors. Antimicrob Agents Chemother. 2013;57(6):2694–2704. doi:10.1128/AAC.00235-13

 PubMed Web of Science ®Google Scholar

Masood F, Yasin T, Bukhari H, Mujahid M. Characterization and application of roxithromycin loaded cyclodextrin based nanoparticles for treatment of multidrug resistant bacteria. Mater Sci Eng C. 2016;61:1–7. doi:10.1016/j.msec.2015.11.076

 PubMed Web of Science ®Google Scholar

Manimekalai P, Manavalan R. Selection of excipients for the formulation of Ceftriaxone sodium loaded chitosan Nanoparticle through drug - Excipient compatibility testing. Int J Res Pharm Sci. 2015;6(2):199–203.

 Google Scholar

Liu X, Li Z, Wang X, et al. Novel antimicrobial peptide—modified azithromycin-loaded liposomes against methicillin-resistant Staphylococcus aureus. Int J Nanomedicine. 2016;11:6781–6794. doi:10.2147/IJN.S107107

 PubMed Web of Science ®Google Scholar