Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 Feb;11(1):53-78.
doi: 10.1007/s40121-021-00559-8. Epub 2021 Nov 22.

Alternative Treatment Strategies for Secondary Bacterial and Fungal Infections Associated with COVID-19

Ritam Das #  1 , Komal Kotra #  2 , Pulkit Singh #  2 , Belinda Loh  3 , Sebastian Leptihn  3 , Urmi Bajpai  4
Affiliations
Review

Alternative Treatment Strategies for Secondary Bacterial and Fungal Infections Associated with COVID-19

Ritam Das et al. Infect Dis Ther. 2022 Feb.

Erratum in

Abstract

Antimicrobials are essential for combating infectious diseases. However, an increase in resistance to them is a major cause of concern. The empirical use of drugs in managing COVID-19 and the associated secondary infections have further exacerbated the problem of antimicrobial resistance. Hence, the situation mandates exploring and developing efficient alternatives for the treatment of bacterial and fungal infections in patients suffering from COVID-19 or other viral infections. In this review, we have described the alternatives to conventional antimicrobials that have shown promising results and are at various stages of development. An acceleration of efforts to investigate their potential as therapeutics can provide more treatment options for clinical management of drug-resistant secondary bacterial and fungal infections in the current pandemic and similar potential outbreaks in the future. The alternatives include bacteriophages and their lytic enzymes, anti-fungal enzymes, antimicrobial peptides, nanoparticles and small molecule inhibitors among others. What is required at this stage is to critically examine the challenges in developing the listed compounds and biomolecules as therapeutics and to establish guidelines for their safe and effective application within a suitable time frame. In this review, we have attempted to highlight the importance of rational use of antimicrobials in patients suffering from COVID-19 and boost the deployment of alternative therapeutics.

Keywords: Antimicrobial peptides; Bacteriophage; COVID-19; Drug repurposing; Nanoparticles; Secondary infections.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1
Schematic representation of drug-resistant secondary infections in SARS-CoV-2-infected patients and the possible alternative therapies. (1) A patient suffering from COVID-19 and other bacterial and fungal secondary infections. (2) Current treatment regimen for secondary infections. (3) Empirical prescriptions and non-compliance with the prescribed antimicrobial course exacerbate the problem of drug resistance. (4) The untapped alternative therapeutic options available that can help combat drug resistance and treat infections
Fig. 2
Fig. 2
Mechanisms of resistance in fungi against antifungal compounds. (1) Fungi tend to overproduce enzymes that are targeted by azoles and other drugs. This prevents the inhibition of vital biochemical reactions. (2) Altering the spatial structure of the targeted enzyme reduces the binding efficiency of azole exponentially. This is a classic case of enzyme-substrate mismatch. (3) Azoles and antifungal drugs are actively pumped out of the cell with the help of efflux pumps. (4) The drugs are not able to penetrate the fungal cell wall/membrane. (5) The cell by-passes the conventional pathway that the drug aims to target. (6) The fungal cells secrete extracellular enzymes that degrade the antifungal compounds
Fig. 3
Fig. 3
Diagrammatic illustration of known antibacterial mechanisms of inorganic nanoparticles (NPs). Inorganic NPs cause membrane damage and form pores causing cytoplasmic leakage and also interruption of electron transport chain and activity of essential bacterial enzymes. Other antibacterial activities of NPs include damage to bacterial DNA and proteins, collectively leading to cell death
Fig. 4
Fig. 4
Therapeutic usage of lytic bacteriophages to treat bacterial infections. The figure illustrates the lytic cycle of bacteriophages and the known methods for their administration for the treatment of bacterial infections
Fig. 5
Fig. 5
Schematic representation of de novo drug discovery vs. repurposing of available drugs. De novo drug discovery and development can take up to 15 years for a drug to be available for clinical use. Drug repurposing by-passes time taken from drug discovery to pre-clinical stage
Fig. 6
Fig. 6
Antifungal action of macrophage-secreted lysozyme and chitotriosidases. Various antifungal enzymes are secreted by the macrophages, for instance, the chitotriosidase cleaves the fungal cell wall and causes the rupture of cells. Other enzymes such as lysozymes, which may be secreted by both neutrophils and macrophages, are said to damage the fungal cell wall, thereby causing an osmotic imbalance leading to cell death
Fig. 7
Fig. 7
Pictorial depiction of endolysin activity on the peptidoglycan layer (PG) of bacterial cells. PG layer here is represented by the repeating units of sugars N-acetylglucosamine (GlucNAc) and N-acetylmuramic acid (MurNAc). For gram-negative bacteria, endolysins (cleavage site represented as Pacman) have to transverse (red arrow) the outer membrane (OM). PG in gram-positive bacteria consists of tetrapeptide chains (blue spheres), which are cross-linked by interpeptide bridges (blue line), while in gram-negative bacteria tetrapeptide bridges are cross-linked by pentapeptide bridges (pink line). IM represents the inner membrane
Fig. 8
Fig. 8
Molecular antibacterial mechanisms of small molecules. Small molecules are known to inhibit bacterial DNA repair mechanisms and enhance bacterial susceptibility to the antibiotic ciprofloxacin, which further induces DNA damage. Also, several other small molecules (example: IMP-1700) are found to be efficacious against pathogens by inhibiting and denaturing the activity of certain essential enzymes required for the survival of the bacteria
Fig. 9
Fig. 9
Screening of novel antifungal small molecules. Wong et al.'s study is a potent example of how novel antifungal molecules are screened from a library of molecules. High-throughput screening (HTS) of a library of 50,240 small molecules was done for Y-H inhibitors, which yielded 20 active compounds that were further validated by assessing their activity in a dose-dependent manner. Eight molecules were identified as potent Y-H inhibitors, which were further analyzed in an antifungal susceptibility test (AST). The four most potent molecules were selected for an anti-biofilm test (ABT), which led to SM21, the most potent of all, that was chosen for further in vitro and in vivo assays
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Manohar P, Loh B, Nachimuthu R, Hua X, Welburn SC, Leptihn S. Secondary bacterial infections in patients with viral pneumonia. Front Med. 2020;7:420. - PMC - PubMed
    1. Mirzaei R, Goodarzi P, Asadi M, Soltani A, Aljanabi HAA, Jeda AS, et al. Bacterial co-infections with SARS-CoV-2. IUBMB Life. 2020;72(10):2097–2111. - PMC - PubMed
    1. Manohar P, Loh B, Leptihn S. Will the overuse of antibiotics during the Coronavirus pandemic accelerate antimicrobial resistance of bacteria? Infect Microbe Dis. 2020;2:87–88. - PMC - PubMed
    1. Fu Y, Yang Q, Xu M, Kong H, Chen H, Fu Y, et al. Secondary bacterial infections in critical ill patients of COVID-19. Open Forum Infect Dis. 2020;7:220. - PMC - PubMed
    1. Udwadia ZF, Tripathi AR, Nanda VJ, Joshi SR. Prognostic factors for adverse outcomes in COVID-19 infection. J Assoc Physicians India. 2020;68(7):56–60. - PubMed

LinkOut - more resources