A review on potential drug delivery system as a treatment of intercellular bacterial infection

  • Madhushreeta Manna Dibrugarh University, Dibrugarh, Assam, India.
  • Arijit Shil West Bengal University of Animal & Fishery Sciences. Nadia, Mohanpur Campus,India.
Keywords: Intercellular bacteria, drug delivery system, drug carriers, liposomes


Introduction: Intracellular bacterial pathogens are hard to treat because of the inability of conventional antimicrobial agents belonging to widely used classes, like aminoglycosides and β-lactams, fluoroquinolones, or macrolides to penetrate, accumulate, or be retained in the mammalian cells. The increasing problem of antibiotic resistance complicates more the treatment of the diseases caused by these agents.

Objectives: The purpose of this chapter is to present the limitations of each class of antibiotics in targeting intracellular pathogens and the main research directions for the development of drug delivery systems for the intracellular release of antibiotics.

Methods: Different improved drug carriers have been developed for treating intracellular pathogens, including antibiotics loaded into liposomes, microspheres, polymeric carriers, and nanoplexes.

Results: In many cases, the increase in therapeutic doses and treatment duration is accompanied by the occurrence of severe side effects. Taking into account the huge financial investment associated with bringing a new antibiotic to the market and the limited lifetime of antibiotics, the design of drug delivery systems to enable the targeting of antibiotics inside the cells, to improve their activity in different intracellular niches at different pH and oxygen concentrations, and to achieve a reduced dosage and frequency of administration could represent a prudent choice. An ideal drug delivery system should possess several properties, such as antimicrobial activity, biodegradability, and biocompatibility, making it suitable for use in biomedical and pharmaceutical formulations. Conclusions: This approach allow reviving old antibiotics rendered useless by resistance or toxicity, rescuing the last line therapy antibiotics by increasing the therapeutic index, widening the antimicrobial spectrum of antibiotics scaffolds that failed due to membrane permeability problems, and thus reducing the gap between increasingly drug-resistant pathogens and the development of new antibiotics.


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Author Biographies

Madhushreeta Manna, Dibrugarh University, Dibrugarh, Assam, India.

Department of Pharmaceutics

Arijit Shil, West Bengal University of Animal & Fishery Sciences. Nadia, Mohanpur Campus,India.

Department of Diploma in Veterinary Pharmacy


Abeylath, S. C., & Turos, E. (2008). Drug delivery approaches to overcome bacterial resistance to beta-lactam antibiotics. Expert opinion on drug delivery, 5(9), 931–949.

Alonso, A., & García-del Portillo, F. (2004). Hijacking of eukaryotic functions by intracellular bacterial pathogens. International microbiology: the official journal of the Spanish Society for Microbiology, 7(3), 181–191.

Institute of Medicine (US) Forum on Microbial Threats. (2010). Antibiotic Resistance: Implications for Global Health and Novel Intervention Strategies. National Academies Press (US).

Baltch, A. L., Bopp, L. H., Smith, R. P., Michelsen, P. B., & Ritz, W. J. (2005). Antibacterial activities of gemifloxacin, levofloxacin, gatifloxacin, moxifloxacin and erythromycin against intracellular Legionella pneumophila and Legionella micdadei in human monocytes. The Journal of antimicrobial chemotherapy, 56(1), 104–109.

Barcia-Macay, M., Seral, C., Mingeot-Leclercq, M. P., Tulkens, P. M., & Van Bambeke, F. (2006). Pharmacodynamic evaluation of the intracellular activities of antibiotics against Staphylococcus aureus in a model of THP-1 macrophages. Antimicrobial agents and chemotherapy, 50(3), 841–851.

Barnewall, R. E., Rikihisa, Y., & Lee, E. H. (1997). Ehrlichia chaffeensis inclusions are early endosomes which selectively accumulate transferrin receptor. Infection and immunity, 65(4), 1455–1461.

Berón, W., Alvarez-Dominguez, C., Mayorga, L., & Stahl, P. D. (1995). Membrane trafficking along the phagocytic pathway. Trends in cell biology, 5(3), 100–104.

Bonazzi, M., & Cossart, P. (2006). Bacterial entry into cells: a role for the endocytic machinery. FEBS letters, 580(12), 2962–2967.

Butts J. D. (1994). Intracellular concentrations of antibacterial agents and related clinical implications. Clinical pharmacokinetics, 27(1), 63–84.

Carlier, M. B., Scorneaux, B., Zenebergh, A., Desnottes, J. F., & Tulkens, P. M. (1990). Cellular uptake, localization and activity of fluoroquinolones in uninfected and infected macrophages. The Journal of antimicrobial chemotherapy, 26 Suppl B, 27–39.

Carryn, S., Van Bambeke, F., Mingeot-Leclercq, M. P., & Tulkens, P. M. (2002). Comparative intracellular (THP-1 macrophage) and extracellular activities of beta-lactams, azithromycin, gentamicin, and fluoroquinolones against Listeria monocytogenes at clinically relevant concentrations. Antimicrobial agents and chemotherapy, 46(7), 2095–2103.

Clemens, D. L., Lee, B. Y., & Horwitz, M. A. (2004). Virulent and avirulent strains of Francisella tularensis prevent acidification and maturation of their phagosomes and escape into the cytoplasm in human macrophages. Infection and immunity, 72(6), 3204–3217.

Cordeiro, C., Wiseman, D. J., Lutwyche, P., Uh, M., Evans, J. C., Finlay, B. B., & Webb, M. S. (2000). Antibacterial efficacy of gentamicin encapsulated in pH-sensitive liposomes against an in vivo Salmonella enterica serovar typhimurium intracellular infection model. Antimicrobial agents and chemotherapy, 44(3), 533–539.

Cuffini, A. M., Tullio, V., Mandras, N., Roana, J., Banche, G., Carlone, N. A. (2004). The leading role of antimicrobial agents in modulating the binomial host-microorganism. Current medicinal chemistry-anti infective agents, 3(1), 1-13.

Deol, P., & Khuller, G. K. (1997). Lung specific stealth liposomes: stability, biodistribution and toxicity of liposomal antitubercular drugs in mice. Biochimica et biophysica acta, 1334(2-3), 161–172.

Desjardins, M., Huber, L. A., Parton, R. G., & Griffiths, G. (1994). Biogenesis of phagolysosomes proceeds through a sequential series of interactions with the endocytic apparatus. The Journal of cell biology, 124(5), 677–688.

Desjardins M. (1995). Biogenesis of phagolysosomes: the 'kiss and run' hypothesis. Trends in cell biology, 5(5), 183–186.

Dijkstra, J., van Galen, M., Regts, D., & Scherphof, G. (1985). Uptake and processing of liposomal phospholipids by Kupffer cells in vitro. European journal of biochemistry, 148(2), 391–397.

Domingo, S., Gastearena, I., Diaz, R., & Gamazo, C. (1995). Significance of environmental conditions (pH and serum) on the in vitro potency of azithromycin against Brucella melitensis. Journal of chemotherapy (Florence, Italy), 7 Suppl 4, 29–31.

Drevets, D. A., Canono, B. P., Leenen, P. J., & Campbell, P. A. (1994). Gentamicin kills intracellular Listeria monocytogenes. Infection and immunity, 62(6), 2222–2228.

Ghigo, E., Capo, C., Tung, C. H., Raoult, D., Gorvel, J. P., & Mege, J. L. (2002). Coxiella burnetii survival in THP-1 monocytes involves the impairment of phagosome maturation: IFN-gamma mediates its restoration and bacterial killing. Journal of immunology (Baltimore, Md. : 1950), 169(8), 4488–4495.

Gregoriadis G. (1995). Engineering liposomes for drug delivery: progress and problems. Trends in biotechnology, 13(12), 527–537.

Gregoriadis G. (1976). The carrier potential of liposomes in biology and medicine (second of two parts). The New England journal of medicine, 295(14), 765–770.

Hackam, D. J., Rotstein, O. D., Zhang, W., Gruenheid, S., Gros, P., & Grinstein, S. (1998). Host resistance to intracellular infection: mutation of natural resistance-associated macrophage protein 1 (Nramp1) impairs phagosomal acidification. The Journal of experimental medicine, 188(2), 351–364.

Hamidi, M., Azadi, A., & Rafiei, P. (2006). Pharmacokinetic consequences of pegylation. Drug delivery, 13(6), 399–409.

Hashim, S., Mukherjee, K., Raje, M., Basu, S. K., & Mukhopadhyay, A. (2000). Live Salmonella modulate expression of Rab proteins to persist in a specialized compartment and escape transport to lysosomes. The Journal of biological chemistry, 275(21), 16281–16288.

Heinzen, R. A., Scidmore, M. A., Rockey, D. D., & Hackstadt, T. (1996). Differential interaction with endocytic and exocytic pathways distinguish parasitophorous vacuoles of Coxiella burnetii and Chlamydia trachomatis. Infection and immunity, 64(3), 796–809.

Hu, C. M., Kaushal, S., Tran Cao, H. S., Aryal, S., Sartor, M., Esener, S., Bouvet, M., & Zhang, L. (2010). Half-antibody functionalized lipid-polymer hybrid nanoparticles for targeted drug delivery to carcinoembryonic antigen presenting pancreatic cancer cells. Molecular pharmaceutics, 7(3), 914–920.

Huynh, N. T., Passirani, C., Saulnier, P., & Benoit, J. P. (2009). Lipid nanocapsules: a new platform for nanomedicine. International journal of pharmaceutics, 379(2), 201–209.

Jain R. A. (2000). The manufacturing techniques of various drug loaded biodegradable poly(lactide-co-glycolide) (PLGA) devices. Biomaterials, 21(23), 2475–2490.

Joralemon, M. J., McRae, S., & Emrick, T. (2010). PEGylated polymers for medicine: from conjugation to self-assembled systems. Chemical communications (Cambridge, England), 46(9), 1377–1393.

Gilbert, P., Collier, P. J., & Brown, M. R. (1990). Influence of growth rate on susceptibility to antimicrobial agents: biofilms, cell cycle, dormancy, and stringent response. Antimicrobial agents and chemotherapy, 34(10), 1865–1868.

Goldberg, M. B., & Theriot, J. A. (1995). Shigella flexneri surface protein IcsA is sufficient to direct actin-based motility. Proceedings of the National Academy of Sciences of the United States of America, 92(14), 6572–6576.

Gregoradis, G. (1993). Liposome preparation and related techniques. In: Gregoriadis G, editor. Liposome Technology. Boca Raton. CRC Press, 1993, 1-63

Gregoriadis G. (1976). The carrier potential of liposomes in biology and medicine (first of two parts). The New England journal of medicine, 295(13), 704–710.

Joshi, A. D., Sturgill-Koszycki, S., & Swanson, M. S. (2001). Evidence that Dot-dependent and -independent factors isolate the Legionella pneumophila phagosome from the endocytic network in mouse macrophages. Cellular microbiology, 3(2), 99–114.

Jung, S. H., Lim, D. H., Jung, S. H., Lee, J. E., Jeong, K. S., Seong, H., & Shin, B. C. (2009). Amphotericin B-entrapping lipid nanoparticles and their in vitro and in vivo characteristics. European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, 37(3-4), 313–320.

Kohane, D. S., Tse, J. Y., Yeo, Y., Padera, R., Shubina, M., & Langer, R. (2006). Biodegradable polymeric microspheres and nanospheres for drug delivery in the peritoneum. Journal of biomedical materials research. Part A, 77(2), 351–361.

Krieger, J., Childs, S., Klimberg, I. (1999). UTI treatment using liposomal amika in Berlin. Clinical Microbiology, 5(Suppl 3),136-144.

Kubica, M., Guzik, K., Koziel, J., Zarebski, M., Richter, W., Gajkowska, B., Golda, A., Maciag-Gudowska, A., Brix, K., Shaw, L., Foster, T., & Potempa, J. (2008). A potential new pathway for Staphylococcus aureus dissemination: the silent survival of S. aureus phagocytosed by human monocyte-derived macrophages. PloS one, 3(1), e1409.

Labro M. T. (2000). Interference of antibacterial agents with phagocyte functions: immunomodulation or "immuno-fairy tales"?. Clinical microbiology reviews, 13(4), 615–650.

Lasic D. D. (1998). Novel applications of liposomes. Trends in biotechnology, 16(7), 307–321.

Mason, N., Thies, C., & Cicero, T. J. (1976). In vivo and in vitro evaluation of a microencapsulated narcotic antagonist. Journal of pharmaceutical sciences, 65(6), 847–850.

Martel, S. (2009). Disadvantage of nanomedicine. International jurnal of nanomedicine, 50, 1– 5.

Medina, C., Rahme, K., Arcy, D. M., et al. (1996). Poloxamer mixed micelles for delivery of gambogic. International journal of nanomedicine, 10, 407-409.

Mingeot-Leclercq, M. P., & Tulkens, P. M. (1999). Aminoglycosides: nephrotoxicity. Antimicrobial agents and chemotherapy, 43(5), 1003–1012.

Mingeot-Leclercq, M. P., Glupczynski, Y., & Tulkens, P. M. (1999). Aminoglycosides: activity and resistance. Antimicrobial agents and chemotherapy, 43(4), 727–737.

Mundargi, R. C., Babu, V. R., Rangaswamy, V., Patel, P., & Aminabhavi, T. M. (2008). Nano/micro technologies for delivering macromolecular therapeutics using poly(D,L-lactide-co-glycolide) and its derivatives. Journal of controlled release : official journal of the Controlled Release Society, 125(3), 193–209.

Nguyen, H. A., Grellet, J., Paillard, D., Dubois, V., Quentin, C., & Saux, M. C. (2006). Factors influencing the intracellular activity of fluoroquinolones: a study using levofloxacin in a Staphylococcus aureus THP-1 monocyte model. The Journal of antimicrobial chemotherapy, 57(5), 883–890.

Portnoy, D. A., Auerbuch, V., & Glomski, I. J. (2002). The cell biology of Listeria monocytogenes infection: the intersection of bacterial pathogenesis and cell-mediated immunity. The Journal of cell biology, 158(3), 409–414.

Prior, S., Gander, B., Blarer, N., Merkle, H. P., Subirá, M. L., Irache, J. M., & Gamazo, C. (2002). In vitro phagocytosis and monocyte-macrophage activation with poly(lactide) and poly(lactide-co-glycolide) microspheres. European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences, 15(2), 197–207.

Roy, C. R., & Tilney, L. G. (2002). The road less traveled: transport of Legionella to the endoplasmic reticulum. The Journal of cell biology, 158(3), 415–419.

Schiffelers, R. M., Storm, G., & Bakker-Woudenberg, I. A. (2001). Host factors influencing the preferential localization of sterically stabilized liposomes in Klebsiella pneumoniae-infected rat lung tissue. Pharmaceutical research, 18(6), 780–787.

Scidmore, M. A., Fischer, E. R., & Hackstadt, T. (2003). Restricted fusion of Chlamydia trachomatis vesicles with endocytic compartments during the initial stages of infection. Infection and immunity, 71(2), 973–984.

Seleem, M. N., Munusamy, P., Ranjan, A., Alqublan, H., Pickrell, G., & Sriranganathan, N. (2009). Silica-antibiotic hybrid nanoparticles for targeting intracellular pathogens. Antimicrobial agents and chemotherapy, 53(10), 4270–4274.

Seral, C., Van Bambeke, F., & Tulkens, P. M. (2003). Quantitative analysis of gentamicin, azithromycin, telithromycin, ciprofloxacin, moxifloxacin, and oritavancin (LY333328) activities against intracellular Staphylococcus aureus in mouse J774 macrophages. Antimicrobial agents and chemotherapy, 47(7), 2283–2292.

Sessa, G., & Weissmann, G. (1968). Phospholipid spherules (liposomes) as a model for biological membranes. Journal of lipid research, 9(3), 310–318.

Sihorkar, V., & Vyas, S. P. (2001). Biofilm consortia on biomedical and biological surfaces: delivery and targeting strategies. Pharmaceutical research, 18(9), 1247–1254.

Sturgill-Koszycki, S., Schaible, U. E., & Russell, D. G. (1996). Mycobacterium-containing phagosomes are accessible to early endosomes and reflect a transitional state in normal phagosome biogenesis. The EMBO journal, 15(24), 6960–6968.

Suzuki, T., & Sasakawa, C. (2001). Molecular basis of the intracellular spreading of Shigella. Infection and immunity, 69(10), 5959–5966.

Swenson, C. E., Popescu, M. C., & Ginsberg, R. S. (1988). Preparation and use of liposomes in the treatment of microbial infections. Critical reviews in microbiology, 15 Suppl 1, S1–S31.

Tewers, F., Boury, F., Benoit, J. P. (2006). Biodegradable Microspheres: Advances in Production Technology. In Microencapsulation: Methods and Industrial Applications. Ed S. Benita. Marcel Dekker, New York.

Torchilin V. P. (2005). Recent advances with liposomes as pharmaceutical carriers. Nature reviews. Drug discovery, 4(2), 145–160.

Tsukano, H., Kura, F., Inoue, S., Sato, S., Izumiya, H., Yasuda, T., & Watanabe, H. (1999). Yersinia pseudotuberculosis blocks the phagosomal acidification of B10.A mouse macrophages through the inhibition of vacuolar H(+)-ATPase activity. Microbial pathogenesis, 27(4), 253–263.

Ulrich A. S. (2002). Biophysical aspects of using liposomes as delivery vehicles. Bioscience reports, 22(2), 129–150.

Van Bambeke, F., Michot, J. M., & Tulkens, P. M. (2003). Antibiotic efflux pumps in eukaryotic cells: occurrence and impact on antibiotic cellular pharmacokinetics, pharmacodynamics and toxicodynamics. The Journal of antimicrobial chemotherapy, 51(5), 1067–1077.

van den Broek P. J. (1989). Antimicrobial drugs, microorganisms, and phagocytes. Reviews of infectious diseases, 11(2), 213–245.

van Ooij, C., Kalman, L., van Ijzendoorn, Nishijima, M., Hanada, K., Mostov, K., & Engel, J. N. (2000). Host cell-derived sphingolipids are required for the intracellular growth of Chlamydia trachomatis. Cellular microbiology, 2(6), 627–637.

Wakiyama, N., Juni, K., & Nakano, M. (1982). Preparation and evaluation in vitro and in vivo of polylactic acid microspheres containing dibucaine. Chemical & pharmaceutical bulletin, 30(10), 3719–3727.

How to Cite
Manna M, Shil A. A review on potential drug delivery system as a treatment of intercellular bacterial infection. jpadr [Internet]. 2020Dec.1 [cited 2023Jun.9];1(2):13-. Available from: https://jpadr.com/index.php/jpadr/article/view/14