How biofilm resistance compares with the COVID-19 response

COVID-19 necessitated lockdowns, testing, repurposing and development of healthcare infrastructure, and streamlining vaccine research and clinical trials.

Countries responded to the pandemic either through the ‘iron dome’ strategy (with international travel bubbles, trade restrictions, testing, quarantine, case isolation and contact tracing); hibernation (restricted public movement, social distancing and lockdowns) or innovation (funds and research to make vaccines, and developing supply chains).

Organized and collaborative human societies made these strategies possible. A bacterial colony’s response to antibiotics has clear similarities.

Much of what we know about bacteria came from studying suspensions growing in a liquid medium where they existed as single cells — every bacterium for itself – called the planktonic mode of life.

But in nature, bacteria predominantly exist as close-knit communities of cells, living within three-dimensional structures of self-produced slime, often attached to an inert or organic surface. This multicellular, community mode of life is called a bacterial biofilm.

Similarly to how cooperative human societies¹ meet challenges and make progress better than any individual can, biofilms develop superior and emergent capabilities often elusive at the individual level. A transition to a multicellular mode upgrades their ability to handle diverse environmental stressors. The two critical enablers of this transition are the biofilm matrix and bacterial communication.

The biofilm matrix spatially segregates bacterial cells, creating differential diffusion of signalling (communication) molecules, nutrients, oxygen and waste. These gradients lead to the formation of different micro-environments within the colony that preferentially sustain particular bacterial variants best adapted to them.

Similarly, quorum sensing and electrical signalling (communication mechanisms) allow establishment of networks and complex relationships between groups of cells in the biofilm. Together, they provide the scaffold for the development of subpopulations, which display coordinated division of labour, orchestrated response patterns, and swarm intelligence.

While similarities can be drawn between the structure² of microbial biofilms and human societies, more striking is the resemblance in their response strategies to external attacks. The way humans faced the COVID-19 outbreak was similar to the way bacterial biofilm fight exposure to antibiotics.

Take the iron dome strategy. In the face of an antibiotic ‘attack’, a biofilm matrix triggers modifications in its structural and functional architecture. These changes transform the colony’s peaceful villa into an armoured fortress.

Biofilm bacteria are inherently more tolerant to antibiotics, compared to their planktonic counterparts, because biofilms act as a diffusion barrier that prevents antibiotics from penetrating the colony. Second, the matrix traps and chemically inactivates the antibiotics that still manage to seep in. Third, efflux pumps and secretion systems actively expel any residual antibiotic from within the biofilm.

During a stress response, these intrinsic capacities of a biofilm are amplified as seen in transcriptomic studies³ reporting upregulation of efflux pumps and matrix modifications such as glycocalyx crosslinking.

The second strategy to hibernate or lie low as ‘persisters’ is even more obvious in a biofilm’s reaction. A small subpopulation of bacteria is reversibly transformed into slowly growing, dormant cells. These are known as persisters or VBNC cells (viable, but nonculturable).

They are generated randomly under normal circumstances, but their proportion dramatically scales up when a biofilm is under attack. Their lower metabolic activity and growth arrest make them less susceptible to antibiotics and confer temporary immunity.

However just like lockdowns, persister phenotypes comprise a low-risk but short-term response, employed in the hope of either a more permanent solution or that the stress (antibiotics) itself will be removed after some time. After this, it is a reversal to the active form for regeneration of the colony.

Hyper-mutators are the innovation, the third strategy. To maintain genome stability under normal circumstances, bacteria reduce their mutation rates through proof-reading and repair mechanisms as well as antioxidant systems. But such mechanisms can be tinkered with to generate a subset of bacteria with very high mutation rates. These bacteria are called mutators.

Mutators are capable of rapidly generating a large pool of variants, which face the antibiotics. This increases the chances for an antibiotic-resistance gene much faster than if mutagenesis were not triggered. Once such a gene is created, the antibiotic-selection pressure prevents it from being overcome by other non-beneficial mutations.

In the same manner in which a successful vaccine candidate is identified and rolled out for an entire population, new resistance genes are distributed throughout the colony. The proximity of cells within a biofilm and horizontal gene transfer mechanisms are ramped up during the adaptive response. Rapid dissemination is ensured.

Increasing mutation rates is a high-risk, high-cost strategy for bacteria. It increases the probability of finding beneficial mutations at the cost of a detrimental accumulation of deleterious ones. But it is a long-term gamble that ensures the survival of the colony — just as a vaccine is expected to function.

Biofilms represent robust microbial societies with exceptional defence and communication systems. Their emergent intelligence and the evolutionary defence strategies are very similar to how organized human communities respond to society-level insults. They are worthy opponents, and the key to our battle against biofilms could lie in understanding how bacterial societies function⁴.