Antibiotics, Resistance, and the Human Microbiome

Toxicity

Direct damage of tissues and organs through the effect of the drugs

Common toxic effects

Digestive issues, Headache, Joint pain

Uncommon toxic effects

Tetracycline → yellow teeth and bones; Ciprofloxacin/Levofloxacin → Light sensitivity

Allergy

Drug acts as an antigen, stimulating an immune response

Microbiome/Biota

Normal microbes in/on healthy body, required for normal host function

Broad-spectrum antimicrobials

Can harm microbiome

Human Microbiome Project (HMP)

Federal funding ending in 2019

Enormous gene pool

Human genome, 21,000 genes → Thousands of proteins; Microbiome genome, 8 million genes → Millions of proteins

Bacterial proteins in gut microbiome

Aid digestion: Amylase - aids starch digestion, Short chain fatty acids production, Gas production, Vitamin synthesis

Packed with viruses

100 million viruses/bacteriophage per gram of feces

Danger lurks

Low numbers of potential pathogens found even in healthy individuals

Link between microbiome and health

Digestive disorders, Diabetes, Mood, Heart disease, Etc, Ability of pathogens to colonize

Types of organisms in microbiomes

Bacteria, Viruses/bacteriophage, Fungus, Protozoa, Archaea

Sources of microbes

In Utero (maybe), Birth, Milk, Caregivers, Environment

C-section vs vaginal birth

Effect on microbiome

Human body as an ecosystem

Has a variety of environmental niches: 37°C, Neutral to acidic pH, Nutrient poor to rich, Normal to no oxygen

Microbiome outcompetes pathogens

Resources competed for: Space, Attachment sites, Nutrients

How the microbiome competes with pathogens

Antibiosis, Taking up space/attachment sites

Normal biota

Defense against incoming pathogens

Superinfection

Over-growth of opportunistic pathogen after destruction of normal community by antibiotic treatment

Examples of superinfection

Candida overgrowth after treatment of UTI

Colonization

The act of taking up long-term residence; as in microbes establishing a steady relationship with a host.

Infection

The entry, establishment, and multiplication of pathogenic organisms within a host.

Disease

Any deviation from health, as when the effects of microbial infection damage or disrupt tissues and organs.

Infectious disease

The state of damage or toxicity in the body caused by an infectious agent.

Pathogen

Parasitic microbe that can cause death and disease.

True pathogens

Capable of causing disease in healthy persons with normal immune defenses.

Opportunistic pathogens

Cause disease when the host's defenses are compromised or when the pathogens become established in a part of the body that is not natural to them.

Pathogenicity

The capacity of an organism to cause disease.

Virulence

The relative capacity of a pathogen to invade and harm host cells.

Virulence factor

Any characteristic or structure of the microbe that contributes to its ability to establish itself in the host and cause damage.

Polymicrobial Infections

Majority of infections are polymicrobial, with contributions from more than one type of microbe.

Infectious dose (ID)

The number of microbes necessary to cause an infection to proceed.

ID50

The amount of organism/virus needed to infect 50% of individuals.

Portal of entry

The route that a microbe takes to enter the tissues of the body to initiate an infection, provides proper environment for growth and spread.

Exogenous

Microbe originating from a source outside the body from the environment or another person or animal.

Endogenous

Microbe already existing on or in the body—normal biota or a previously silent infection.

Sequential infections

Influenza infection frequently leads to pneumonia.

Antimicrobial treatment

The use of drugs to treat infections caused by microbes.

Interactions between drug and microbe

The effects that drugs have on microbial organisms.

Bacteria

Single-celled organisms that can cause infections.

Fungus

A group of organisms that includes yeasts and molds, some of which can cause infections.

Protozoa

Single-celled organisms that can cause diseases in humans.

Helminths

Parasitic worms that can infect humans.

Viruses

Infectious agents that require a host cell to replicate.

Antimicrobial resistance

The ability of certain microbes to tolerate an amount of drug that would normally be inhibitory.

Interactions between drug and host

The effects that drugs have on the host organism.

The human microbiome

The collection of microorganisms living in and on the human body.

Viruses rely on a host cell

Viruses depend on host cells for most of their metabolic functions.

Vaccines

Biological preparations that provide immunity to a particular disease.

Inhibit entry

Preventing a virus from entering a host cell.

Inhibit replication, transcription and translation

Stopping the processes by which viruses reproduce and create proteins.

Inhibit viral assembly/release

Preventing the virus from assembling or being released from the host cell.

Fuzeon

A drug that blocks HIV binding to cell receptors.

Relenza

An antiviral that blocks membrane fusion.

Tamiflu

An antiviral that blocks membrane fusion.

Remdesivir

An antiviral that blocks RNA replication (SARS-CoV-2).

AZT

A nucleotide analog that blocks reverse transcriptase (HIV).

Nevirapine

A drug that blocks reverse transcriptase.

Indinavir

An antiviral that inhibits HIV protease enzymes and blocks assembly.

HIV PrEP

Pre-exposure Prophylaxis; the use of a drug to prevent infection of a person at risk.

Drug resistance

The ability of certain microbes to tolerate an amount of drug that would normally be inhibitory.

Genetic variability of microbial populations

The differences in genetic makeup among microbial organisms that contribute to drug resistance.

Chromosomal mutations

Spontaneous mutations in critical chromosomal genes that lead to drug resistance.

Horizontal Gene Transfer

Acquisition of entire new genes or sets of genes that can confer drug resistance.

Resistance (R) factors

Plasmids containing antibiotic resistance genes.

Beta-lactamases

Enzymes that cleave the beta-lactam ring of the penicillin family of antibiotics, also known as penicillinases.

Decreased permeability

A mechanism of drug resistance where the transport protein is mutated to no longer transport the drug.

Efflux

A mechanism where the drug is immediately pumped back out of the cell.

Multi-Drug Resistant (MDR) pumps

Pumps that expel multiple drugs from the cell, contributing to drug resistance.

Binding site alteration

A mechanism where the binding site for the drug is decreased in number or affinity.

Altered metabolic pathways

A mechanism where alternate pathways to folic acid synthesis result in resistance to sulfonamide and trimethoprim.

Natural Selection and Drug Resistance

In large populations, resistant mutants have a selective advantage when exposed to drugs, leading to the dominance of drug-resistant strains.

Persisters

Cells with slowed or stopped metabolism that can be resistant to antibiotics.

AntiMicrobial Resistance (AMR)

The phenomenon where many infections treated with antimicrobials become resistant to most or all drugs.

Phage Therapy

A treatment method using phage infection that is more specific than antibiotics.

RNA interference

Small RNA molecules that prevent mRNA translation.

Defense peptides

Small peptides made by the host immune system or bacteria that attack bacteria or viruses.

CRISPR

A technology to alter the genome of a pathogen, making it susceptible to antibiotics.

Probiotics

Mixtures of live microbes fed to humans or animals to replace or augment lost microbes during antimicrobial therapy.

Prebiotics

Nutrients that encourage the growth of beneficial microbes in the intestine.

Fecal transplants

A treatment method used to transfer feces from a healthy patient to treat recurrent Clostridium difficile infection and ulcerative colitis.