Foscarnet is a pyrophosphate analog that inhibits DNA polymerase by simply preventing the pyrophosphate-binding site of the viral DNA polymerase. The mechanism of action of this drug uniquely helps combat antiviral drug resistance because viral resistance to nucleoside analogs is linked to mutations aimed at reducing or ending phosphorylation of the drug in virus-infected cells [17] . This drug is used to treat ganciclovir-resistant cytomegalovirus (CMV) infections in patients with acquired immunodeficiency syndrome (AIDS) or in transplant recipients. [18] . Clinically, Foscarnet is used exclusively for treatment of CMV-resistant and acyclovir resistant herpes simplex virus (HSV) and varicella zoster virus (VZV). In some cases, such as CMV-encephalitis, foscarnet could be used in combination with ganciclovir. These drugs have adverse effects such as nephrotoxicity and encephalopathy with acyclovir while ganciclovir is associated with myelosuppression, particularly neutropenia, nephrotoxicity and electrolyte abnormalities [18] .

Drug resistance of infectious disease-causing agents like viruses is a critical concern to global public health. The use of antibiotics by humans is fraught with a major challenge of over-exposure of bacterial strains inherently present in the digestive and respiratory tracts indiscriminately to antibiotics [19] . Exposure to more antibiotics than needed by the body makes an individual a carrier of resistant pathogens that could potentially spread with time becoming problematic during surgeries or immunosuppression. Microorganisms -bacteria, mycobacteria, parasites, fungi and viruses have for several millions of years developed resistant mechanisms by developing genes that code for resistance to various threats such as heavy metals and antimicrobial compounds such as beta-lactamspenicillin, carbapenems, fluoroquinolones and sulphonamides [20] . Examples of AMR is seen in the buildup of resistance to colistin, an antibiotic that was once very effective for the treatment of multi-drug resistant Gram-negative bacteria is now widely reported as resistant with Enterobacteriaceae species [21] . In the treatment of fungal infections, drug resistance to azole derivatives like ketoconazole, fluconazole, itraconazole and voriconazole by Aspergillus species, Cryptococcus neoformans, Candida species and Trichosporon beigelli [22] .

Multi-drug resistant E. coli, Staphylococcus aureus, K. pneumoniae, S. pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa cause millions of deaths annually because of antimicrobial drug resistance [23] . According to WHO 2022 over 50% resistance was reported for bacterial infections caused by Klebsiella pneumoniae and Acinetobacter spp., globally [24] . In 2019, the total number of deaths attributed to antimicrobial resistance globally is 4.95 million and if urgent measures are not taken now, the estimate could double [24] . Chloroquine is a semisynthetic derivative of quinine, the first drug initially used to treat malaria and it relies on membrane-bound transporter proteins and became ineffective with time and replaced with artesunate and artemisinin due build up chloroquine resistant parasites [25] [26] .

The economic consequences of drug resistance can be severe, and one estimate suggests that from 2000 to 2050 global losses due to resistant infection could be over 100 trillion US dollars [24] . According to this report, the World Bank estimates that up to 3.8% of the global gross domestic product could be lost because of AMR by 2050 and health care costs estimated to be up to I trillion US dollars by the year 2030 annually [24] .

There is always the fact that new viruses like Ebola, coronaviruses (SARS-CoV-2) can emerge further complicating managing viral infections. A good understanding of the mechanisms, factors and consequences of antiviral drug resistance is needed for developing effective therapies and mitigating its impact. It is therefore imperative that effective and safe drugs are used because infectious viruses like HIV, Hepatitis B and C can be potentially lethal leading to death and as such natural products are under consideration as they are adjudged to be safe and effective [27] . The major reason given for the development of antiviral drug resistance is continued use of antiviral agents that do not clear the viral load and successful viral replication in individuals with low immune systems despite treatment [28] . A typical example is seen in the treatment of viral infections that takes prolonged periods, in some cases months and years as seen in HIV and the viruses that survive the treatment regime evolve and proliferate after mutating to more virulent strains [29] . Viral mutations cause changes in their genetic code particularly genes that code for viral proteins targeted by antiviral agents resulting in alterations in their amino acid sequences [6] . The exposure of viruses to different antiviral agents creates selective pressure on the virus population particularly with individuals that cannot clear viral loads with administered drugs, presenting a drug-resistant population [30] . The concentration of antiviral compounds in the system of patient might not be enough to clear the viruses completely for various reasons leading to insufficient drug concentrations which gives the virus selective advantage that could lead to the buildup of resistance to the drugs [29] . Cross-resistance is a factor that contributes to antiviral drug resistance for example if a drug targets reverse transcriptase and a virus exposed to it develops resistance to it, the progeny of this virus will be resistant to another member of this class of drug leading to cross-resistance. This therefore limits the effectiveness of multiple drugs against a resistant viral serotype [31] . Viruses can also develop resistance by modifying the target sites of antiviral drug compounds. This modification could involve structural changes in viral enzymes and receptors that make the binding sites on them unavailable to the drugs. E.g., with the treatment of HIV, resistance to reverse transcriptase inhibitor can occur through changes to the viruses’ reverse transcriptase active sites. The virus could alter the expressions of functions of the activating enzymes rendering them useless and the drugs mechanism of action ineffective [32] . Viral recombination events occur very fast, and the pool of genes is so much that it is difficult to keep up with the exchange of materials and buildup of new variants. It is an established fact that gene reassortment might lead to over two hundred and fifty genetically viral progenies, making it apparent that influenza viruses are a great threat to public health [33] . Some viruses like HIV show long-term persistent infections providing extended time for development and selection of drug-resistant variants. Here, the main factor that leads to development of resistance by the viruses to drugs is the fidelity of viral replication, which is extremely high in double-stranded DNA viruses [34] . Enhanced drug efflux can cause of drug resistance as some viruses can develop strategies/mechanisms for pumping out antiviral compounds out of the infected cells and as such reducing the drugs concentration intracellularly [35] .

Resistance to HIV-2 virus along with other direct-acting antivirals for treating viral infections like those of HBV, HCV, influenza, HSV, varicella zoster virus (VZV) and CMV is an established fact [36] . Common viral infections like the influenza viruses (H1N1) have shown resistance to drugs like oseltamivir used for treatment with the concomitant effect of loss of lives and economic loss from the cost of failed medication [37] . The consequences of antiviral drug resistance range from exposure to toxicity inherent in the use of second-line antivirals, to increased severity of disease symptoms and even death because of progression of viral infection when no effective alternative treatments are available.

Antiviral drug resistance is very problematic particularly with immunocompromised and immunosuppressed individuals because there is continued viral replication and the prolonged drug exposure results in the development of resistant serotypes. Resistance to drugs like acyclovir has mostly been with immunosuppressed and immunocompromised individuals. The mechanism of HSV to acyclovir is through viral thymidine kinase (TK) or DNA polymerase mutation. TK mutation could result in deficient virus not responsive to the drug of choice and resistance has also been linked to TK substrate specificity. Cross-resistance to other drugs like penciclovir is expected with TK deficient mutants [12] .

In the hospitals, acyclovir-resistant HSV infections are treated with foscarnet with success. CMV resistance to the drug ganciclovir is characterized by mutation in the viral gene UL97 kinase, which is capable of decreasing phosphorylation of ganciclovir, rendering it impotent. Drugs approved for treatment of hepatitis B infections are nucleoside analogs (lamivudine) and nucleotide analogs (tenofovir) and these target the HBV DNA polymerase and these drugs require prior phosphorylation by cellular enzymes. HBV infections are treated using combinational therapy because of antiviral drug resistance. Mutations in the reverse transcriptase domains of the viral polymerase gene are responsible for development of resistance to these drugs. High degrees of lamivudine resistance has been attributed to tyrosine-methionine-aspartate-aspartate motif in the C domain of the polymerase gene [12] .

The resistance of HIV to drugs like zidovudine and lamivudine was prevalent and this led to the introduction of combination therapies for the treatment of HIV-1 and HIV-2 infections. The main mechanism of resistance is mutation in the reverse transcriptase gene which affects the drug binding sites and polymerase activity [9] . Fostemsavir (formerly GSK-3684934) is a first-in-class oral attachment inhibitor binding to gp 120. It is to be used in combination with other antiretroviral drugs for the treatment of HIV-1 infection in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection in whom current treatment failed due to resistance, intolerance, or safety considerations. Records show that Fostemsavir-associated resistance does not result in cross-resistance to other entry or attachment inhibitors such as ibalizumab and maraviroc [16] .

Ibalizumab is a humanized monoclonal antibody and noncompetitive CD4 post-attachment inhibitor with approval for the treatment of patients with multiclass drug-resistant viruses. This is because the mechanism of attachment for this drug requires a previous attachment of HIV-gp 120 to the CD4 receptor and it therefore does [38] . There are no recorded mutations to this drug and as such genotypic testing to predict resistance is not recommended [16] .

The use of nano-compounds in designing antiviral agents will also potentially improve the efficiency of the drugs, time of action and ensure that dosages are sufficient to hit target sites minimizing the risk of resistance due to prolonged exposure [17] . There are seven main classes of antiviral drugs currently been used based on broad spectrum activities, and they are neutralizing antibodies, neutralizing recombinant soluble human receptors, antiviral CRISPR/Cas systems, interferons, antiviral peptides, antiviral nucleic acid polymers and antiviral small molecules [39] . The use of RNA-targeted therapies that interfere with viral RNA replication or its translation will potentially disrupt essential RNA functions that can hamper the progression of the disease in the host cells [39] .

The bioactive compound in plants, algae, animals, marine organisms, and microbes have very complex and intricate chemical compositions because they are derived from natural selection or evolutionary pressures of adaptation, making these organism huge deposits for medicinally valuable molecules. Paclitaxel isolated from the plant Taxus brevifolia in the early 70s is currently being used for treating cancer [40] . The compound Leonurine, extracted from the plant Herb leonuri displays broad-spectrum activities such as antioxidant, antiapoptotic and anti-inflammatory potentials [7] . The popularity of drug discovery from natural sources is clear from the fact that more than 60% of low molecular weight drugs discovered in the past two decades are from natural source [41] .

Antiviral drug discovery is based on interception and stoppage of viral growth at various stages directly from outside the cell, disrupting attachment to cellular receptors. Cholesterol and some rare forms of lipids utilized for viral replication and apoptotic processes could be targets for combating viral infection during antiviral drug discovery [42] . For example, with human enteroviruses, several compounds (such as benzothiopene derivatives) have been designed to fit into special hydrophobic pocket, replacing the aliphatic fatty acids that normally house the viral particle [42] . This pocket is important because it is close to the receptor binding area and as such capable of targeting the ability to bind to receptors at such sites [43] . Virus groups that use similar receptors to bind, could be targeted with specific compounds preventing viral infection [44] . Some drugs target cytoplasmic endosomes used by viruses as their main portal for entering cells and are particularly effective against non-enveloped viruses [45] . Targeting translation and transcription mechanisms of RNA-based viruses could be an effective way of stopping their infection process [46] . Strategies for antiviral drug discovery should also involve targeting membranous structures used by DNA viruses for replication at the surface [47] .

The synthetic antiviral agents initially used were toxic at therapeutic doses and as such the natural products seem to be better options. Interest in the use of natural products as antiviral agents was initially limited by the fact that screening, purification, and identification of antiviral compounds in crude extracts was very cumbersome. The renewed surge in the use of natural compounds as a source of antiviral agent stems from the fact that the technology for detection, isolation and structural characterization of these compounds has greatly improved. There are bioactive compounds from natural sources and derivatives of these compounds that have antiviral properties [48] . The phytochemicals (secondary metabolites) that have been implicated in antiviral activity are listed in Table 1 below and broadly, these include alkaloids, flavonoids, glycans, organic acids, terpenoids, phenolics, terpenoids, tannins anthocyanins and flavones and potentially have broad spectrum effects with their activities varying with the species from which they are isolated or extracted [49] .

Polysaccharides of algal origin with antiviral effects abound and they include carrageenan, alginate, fucan, laminaran, and naviculan [82] . These polysaccharides have different mechanisms of action as antiviral agents ranging from inhibiting binding and internalization of viruses to host cells to suppressing viral DNA replication and protein synthesis [82] .

Carrageenan: Previous studies have shown that this sulphated polysaccharide extracted from red algae from the genera Chondrus, Gigartina, Hypnea and Eucheuma inhibited viral activity (rhinovirus, human papillomavirus) by preventing adsorption and attachment to host cells [83] . Carrageenan isolated from Gigartina skottsbergii potentially active against influenza virus, DENV, HSV-1, HSV-2, HPV, HRV and HIV viruses. They are extremely effective against sexually transmitted HPV types that lead to cervical cancer and genital warts (human papillomavirus) [83] . Extracts from Polysiphonia denudata (a red marine algae) showed inhibitory effects by preventing adsorption and intracellular stages of the replication of HSV-1 and HSV-2 at an effective concentration of 8.7mg/ml [84] . Terpenoid compounds extracted from red macroalgae -Dictyota pfaffi and Dictyota menstrualis also demonstrated anti-HIV activity with low toxicity [84] .

Galactan: Some Galatans (extracellular sulfated polysaccharides structurally different from carrageenan) extracted from the following red algae-Callophyllis variegata (an edible seaweed), Agardhiella tenera, Schizymenia binderi, Crytonemia crenulata recorded activity against HSV-1, HSV-2, HIV-1, HIV-2, DENV and HAV viruses [83] . Mechanism of action in HIV-1 & 2 infection is prevention adhesion of the virus to cell and attachment of gp 120 on CD4+ T cell receptor to HIV-1 gp 120 [85] .

Alginates: The marine polysaccharide 911 is an alginate polysaccharide that showed strong activity against HIV-1 at both chronic infection stages of H9 cells and acute infections of MT4 cells in both in vitro and in vivo experiments [86] .

Fucan and Fucoida. Sulfated fucans (high molecular weight polysaccharide) from Dictyota mertensii, Lobophora varietgata, Fucus vesiculosus and Spatoglissum shroederi have been used to prevent HIV infection through blocking of the reverse transcriptase activity- [87] . Another fucan polysaccharide isolated from Cladosiphon akamuranus inhibited DENV-2 infection in BHK-21 cell line, while MC26 is a fucose polysaccharide isolated from Sargassum piluiferum with strong anti-influenza virus activity and low cytotoxicity [88] .

Fucoidans are biologically active against HIV, HSV-2, Dengue virus and cytomegalovirus blocking interaction of viruses with cells preventing viral induced syncytium formation [88] . Fucoidans extracted from species like Stoechospermum marginatum and Cystoseira indica showed potential antiviral activity against Newcastle disease in Vero cell line [88] . Polysaccharides (ulvan and fucoidan) from sea weeds Ulva clathrata and Cladosiphon okamuranus could inhibit viral attachment and cell fusion in Newcastle Disease virus (NDV) infection [87] . Other sulfated fucans from genera of brown sea weeds Dictyota mertensii, Lobophora variegata, Fucus vesiculosus and Spataglossum schroederi successfully blocked reverse transcriptase activity in HIV infection [88] . The most prominent broad spectrum antiviral agents of algal origin are the lectins Cyanovirin and Griffithsin from Nostoc (a cyanobacterium) and Griffithsia (red alga) species respectively [88] .

Laminarin: Laminaran is a glucan abundant in some species of brown algae like Saccharina longicruiris and Ascophyllum nodosum, an effective inhibitors of HIV replication and proliferation. The mechanism of action is via prevention of adsorption of HIV onto human-derived lymphocytes and HIV reverse transcriptase [87] .

Naviculan: This is a sulfated polysaccharide from the diatom Navicula directa with activity against HSV-1 and HSV-2 at a low IC₅₀ value <14 µg/ml and the influenza virus by inhibiting the initial stages of viral replication and potentially blocking viral internationalization into host cells [89] .

Calcium Spirulan: Another polysaccharide extracted from the marine blue-green algae (Cyanobacteria) Arthrospiroa (Spirulina) platensis capable of inhibiting HSV-1 (in HeLa cells); HCMV (in HEL cells), influenza A (in MDCK cells) [90] .

The polysaccharide calcium spirulan extracted from Arthrospira platensis showed broad spectrum activity against the following viruses: HSV-1, human cytomegalovirus (HCMV), measles virus, mumps virus, influenza A and HIV-1 by preventing viral penetration into host cells. While nostoflan isolated from Nosctoc flagelliforme (a cyanobacterium) prevented adsorption of the same viruses (HSV-1; HSV-2; HCMV and influenza virus A at maximum inhibitory doses of 0.37, 2.9, 0.47 and 78 µg/mL respectively [91] . Exopolysaccharides of other bacteria species like Streptococcus thermophilus had another mechanism of action against viruses by activating the Toll-like receptor S and expression of interferons in porcine intestinal epithelial cell that are responsible for innate antiviral immune response [92] .

High molecular weight polysaccharides extracted from Porodaedalea pini are capable of reducing plaque formation by herpes simplex virus 1 (HSV-1) at an effective dose of 5 g/mL in Vero cells. Another polysaccharides (EP-AV2) with a lower molecular weight reduced plaque formation the coxsackie virus B3 (CVB3) in HeLa cells at an effective dose of 1 mg/mL [93] . Protein-bound polysaccharides from Ganoderma lucidum a medicinal mushroom were active against HSV-1 and HSV-2 [94] . The acidic protein-bound polysaccharide was more reactive than the neutral one at EC₅₀ concentrations <100 µg/ml [94] . Lentinan a polysaccharide from Lentinus edodes inhibited the infectious hematopoietic necrosis virus (IHNV) by immediate inactivation and viral replication limitation [95] . Acidic polysaccharides from Cordyceps militaris reduced the viral titer of influenza virus (H1N1) in the bronchoalveolar area and lung of mice while increasing the TNF-α and interferon (IFN) levels in the blood [96] . Agaricus blazei polysaccharide (ABP-AW1) reduced CPE of Western equine encephalitis virus while sulfated polysaccharides from Agaricus brasiliensis inhibited HSV-1 and acyclovir-resistant strains 29R [97] . Tyrosinases-proteins isolated from Agaricus bisporus showed antiviral activity against Hepatitis C virus by catalyzing selective hydroxylation of crucial position tyrosine residues in viral proteases [98] . GLPG a proteoglycan isolated from Ganoderma lucidum inhibited Herpes simplex virus types 1 and 2 in a dose-dependent manner with no cytotoxic effect even at high concentrations (2000µg/ml). Polysaccharide (AHCC) extracted from Lentinus edodes mycelium showed broad-spectrum antiviral activity inhibiting West Nile Virus, influenza virus, hepatitis virus and human papillomavirus [99] [100] . Lentinan (LNT-1) extracted from Lentinus edodes inhibited IHNV infection progression in cells by direct inactivation and inhibition of viral replication [101] .

Polysaccharides of the plant Chuaminshen violaceum were active against Newcastle disease virus (NDV) by inhibition of viral adsorption and penetration into cells [102] . A mixture of five highly branch polysaccharide-protein conjuncts (LbGp1-5) extracted from Lycium barbarum showed antiviral and immunomodulatory effects on H1N1-induced viral pneumonia in in vivo and in vitro tests by blocking viral attachment and entry, reducing viral load in lung, regulating the phenotype of pulmonary macrophages and inhibiting excessive inflammation [103] . Another sulfated polysaccharide from the plant Caesalpinia ferrea showed effects against Herpes simplex virus (HSV) and Poliovirus (PV) by inhibiting virus adsorption, and synthesis of viral proteins and had the promising effect of low cellular toxicity [104] . Achyranthes bidentata polysaccharide sulfate (ABPS) isolated from showed activity against porcine reproductive and respiratory syndrome virus (PRRSV) at low concentrations [105] . Other polysaccharides extracted from the plant Portulaca aleracea showed inhibitory effects against Herpes simplex virus type 2 (HSV-2) and influenza virus a (IFV-A) with the pectic polysaccharides outperforming the acidic and neutral polysaccharides. The drug PG2^® lyophilized injection is an injectable product containing an active fraction of polysaccharide which was extracted, and purified from the roots of Astragalus membranaceus that has been used for the treatment of COVID-19 with success [106] . It is now known that PG2 can upregulate microRNAs having antiviral potential and anti-inflammatory ability of macrophages, thereby driving M2 macrophage polarization and improving the inflammatory lung microenvironment [107] . In 2019, our lab demonstrated that certain components of Zanthoxylum armatum and Hibiscus sabdariffa show antiviral effects, especially against the norovirus [100] .

Animals: There are more than eleven animal toxins such as the cone snail peptide (ziconotide), two lizards’ peptides (exenatide and lixisenatide) two leech peptides (bivalirudin and desirudin) and six snake venom-related drugs (captopril, cabrotide, enalapril, eptifibatide, tirofiban and batroxobin) has officially been sold as drugs in the market [101] .

Scorpion: There are studies that document the antibacterial, anticancer, and antiviral properties of these small peptides isolated from scorpion venom [102] . There are numerous antiviral scorpion peptides classified as small molecule NDBPs that have been identified such as Ctry2459, Hp1090 and mucroorin-M1 [103] .

The scorpion peptide -Ctry2459 extracted from Chaerilus tryznai has been reported to be active against HCV by inactivating infectious viral particles, but the toxin Hp1090 isolated from Heterometrus petersii caused direct inhibition by permeating the viral phospholipid membrane [104] [105] . Another histidine rich peptide -Eval418 isolated from Euscorpiops valifus had broad spectrum effect on HCV and HSV-1 [104] [105] . The mucroporinM1 showed remarkable broad-spectrum activity against measles, SARS-CoV, influenza, H5N1 virus and HBV infections [103] . Scorpion venom compounds have been reported to have the ability of their disulfide-bridged peptides (DBPs) to bind to HIV gp 120 glycoprotein because they mimic lentiviruses host cell CD4⁺ receptor cells [106] . They can therefore stop the gp-CD4 interaction, an essential component with the capacity viral entry to host cells [57] .

Snake: Snake venom has also been implicated in antiviral activities specifically against measles, Sendai virus, dengue virus, yellow fever virus and HIV and been demonstrated in clinical trials [107] . The antiretroviral activity of snake venom was attributed to effect on HIV-1 glycoprotein or protease with the ability to decrease viral load and T CD4⁺ cell count [107] . Novel studies reveal that snake Phospholipase A2, (PLA2s) function as antiviral agents by inhibiting syncytium formation between HIV-infected cells and healthy CD4⁺ cells, preventing HIV from binding to cells. The study also showed that only (Phospholipase A2) PLA2s that are dimeric have virucidal effects and they do this by destruction of the viral membrane [108] .